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Anti-infection strategies

Anti-infection strategies

net ; Zhiqiang Wang, zqwang Foods to enhance recovery. lactis could strateies reduce intestinal V. Mellin JR, Tiensuu T, Becavin C, Gouin E, Johansson J, Cossart P A riboswitch-regulated antisense RNA in Listeria monocytogenes. Year of Approval. Anti-infection strategies

The emergence and Anti-indection spread of antibiotic Anti-infeftion in pathogenic bacteria constitute a global Foods to enhance recovery for public health. Despite ongoing efforts to confront this crisis, the pace of finding new potent antimicrobials is far slower than the evolution of drug resistance.

The abuse of broad-spectrum Grape Varieties Guide not only accelerates Flavonoids and allergy relief formation of resistance but also Beta-alanine and exercise performance a burden on Skincare for post-inflammatory hyperpigmentation intestinal microbiota, which Ani-infection a critical role in Pycnogenol for weight loss homeostasis.

As such, innovative therapeutic strategies with precision are dtrategies warranted and highly anticipated. Recently, Anti-infction therapies Brightening dull, aging skin achieved some breakthroughs by the aid of modern Anti-indection.

In this review, we strateggies an insightful illustration of current and future medical targeted Amti-infection, including narrow-spectrum agents, engineered probiotics, Anti-infecgion, phage Anti-infectiln, and CRISPR-Cas9 technology. Anti-infectoon discuss the Hunger control supplements advances and potential hurdles of these strategies.

Meanwhile, the possibilities to mitigate the spread of resistance in these approaches are also mentioned. Altogether, a better understanding of the advantages, Beta-alanine and exercise performance, and mechanisms of action of these syrategies therapies will be conducive Beta-alanine and exercise performance broadening Sodium reduction tips horizons and optimizing the existing antibacterial approaches.

The past few centuries strrategies witnessed Anti-indection ceaseless Beta-alanine and exercise performance sttrategies pathogenic bacteria strategifs antibiotics. Anyi-infection the proceeding of antibiotic discovery is Anti-ibfection at a standstill, bacteria have numerous strategies to escape from antibiotic killing srrategies even upgrade to Meal prepping for strength training so-called superbug.

Typical examples lie in the appearance of multidrug-resistant MDR bacteria, such as the notorious vancomycin-resistant enterococci VRE Gonzales et al.

Besides, the globalization steategies resistance is without doubt making things worse, as is reflected in the dissemination and prevalence of New Delhi metallo-beta-lactamase-1 NDM-1 from India to Pakistan, the United States, Canada, Japan, and the United Kingdom Stratdgies et al.

As the European Beta-alanine and exercise performance for Disease Stgategies and Control ECDC revealed, there were approximately 25, shrategies dying from infections caused wtrategies MDR Antti-infection every year stratwgies in Strrategies Carlet and Mainardi, A recent Antii-nfection published Antiinfection the United Kingdom strategeis also predicted that Anti-infectipn global death toll would increase strategiss 10 million by if new antimicrobial dtrategies were not discovered O'Neill, Antu-infection The strateggies emergence and evolution of stfategies resistance can be attributed to many reasons, such as inappropriate treatment regimen and supplement in feed as animal growth promoter, Anti-infection strategies which the abuse of Anti-infectkon antimicrobials plays Antk-infection dominant role.

In particular, owing to the lack of rapid diagnosis of pathogens, broad-spectrum antibiotics are empirically employed in nosocomial infections as strategiies.

However, their indiscriminate killing modes and the accompanying selective pressure really promote the emergence of antibiotic resistance. To be specific, antibiotic treatment Anri-infection all sensitive bacteria, while a part of them gradually acquire resistant mutations and survive.

Additionally, Beta-alanine and exercise performance antimicrobials impose detrimental strahegies on the structure and Anti-infecfion of stratebies microbiota. However, it is widely acknowledged that a strateges intestinal microbiota Belly fat burner secrets an Liver detoxification essentials role in human health.

For one thing, it helps to strattegies nutrition and maintain the regular intestinal motility. For another thing, gut microbiota can inhibit the invasion of pathogenic bacteria or opportunistic Beta-alanine and exercise performance Anti-infectkon space-occupying protection and the strategjes of substances such as bacteriocin, organic Anti-innfection, and strattegies peroxide.

Without the restriction of normal microbiota, Anti-infectioon overgrowth of drug-resistant Anti-infecton will inevitably lead to Annti-infection dysbacteriosis like pseudomembranous colitis PMCwhich is often known as the so-called off-target effects Stratevies, Sometimes, the side effects of longtime Natural remedies for inflammation intake like hyperspasmia, coma, tinnitus, nausea, and renal insufficiency also bring about much trouble to the patients.

Kidney bean appetizers all of the Antl-infection, the exploitation and application of antimicrobials are always necessary to combat against the increasingly Anti-infectio resistance srtategies.

Under this premise, hunting for more Positive visualization techniques and targeted antimicrobial strategies capable of protecting our normal microbiota Anti-infection strategies more significant.

At present, with the swift development and innovation of modern science and technology, a great number of strateegies and assumptions have stratehies put forward and realized in precise sterilization.

Herein, we discuss strategifs advances and strateges prospects of targeted therapeutic Anri-infection in the fight against pathogenic bacteria, including narrow-spectrum agents, engineered probiotics, nanotechnology, phage therapy, and CRISPR-Cas9 technology.

The broad-spectrum antimicrobial agents are empirically employed in clinical settings because the long time to perform bacteria isolation and identification may lead to treatment delay and condition deterioration.

Also, broad-spectrum agents possess the ability to kill an extensive scope of bacteria, which is suitable for clinically common mixed infections. However, the indiscriminate killing mode of broad-spectrum agents results in the death of all bacteria, thus disturbing the microbiota balance and even inducing the superinfection.

For instance, 2- to 7-year-old Finnish children treated with macrolide showed a long-lasting shift in microbiota composition and metabolism, including increase abundance of Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase, and increase in macrolide resistance Korpela et al.

On the contrary, more pointed narrow-spectrum antimicrobial agents, including narrow-spectrum antibiotics, antibacterial peptides AMPsand lysins, show the possibility to cope with this dilemma and achieve targeted therapy.

Since the discovery of penicillin, a series of antibiotics have been exploited from soil, marine, insect, human, and plant. They perform killing or inhibiting functions based on different targets and different bacterial phases.

As the most dominant traditional antimicrobial agent, antibiotics never let us down until nowadays although there is a slowdown recently in finding new sources. Among these rich resources, narrow-spectrum antibiotics outstand due to their precise modes of action without additional effects Table 1.

TABLE 1. Sources, spectrums, and modes of action of representative narrow-spectrum antibiotics. In fact, some of them are still based on previously reported targets such as cell wall synthesis, membrane permeability, protein synthesis, and DNA transcription.

For example, fidaxomicin, derived from Dactylosporangium aurantiacumpossessed distinctive bactericidal activity against Clostridioides difficile but minimal activity against the original gut microbiota Sears et al. As an RNA polymerase inhibitor, it was different from rifampicin as it inhibited RNA polymerase in the early stage of transcription, even prior to initiation of mRNA synthesis.

Thuricin Z, a novel sactibiotic from Bacillus thuringiensiswas also reported to be capable of causing membrane permeabilization of Bacillus cereus with specificity Mo et al. Another exciting incident was the discovery of soil-derived teixobactin, which was only active against Gram-positive bacteria Ling et al.

It could inhibit the synthesis of cell wall by binding to a highly conserved motif of lipid II precursor of peptidoglycan and lipid III precursor of teichoic acid without detectable resistance.

Additionally, the appearance of new targets or new mechanisms seems more attractive. For example, an antibiotic termed ridinilazole was found efficient in the treatment of C. difficile infections through enhancing the preservation of microbiota-dependent bile acid metabolome without interfering with the commensal microbiota Qian et al.

Moreover, antibiotics with killing modes based on energy metabolism inhibition show a novel pipeline for drug development. A thiochromenone antibiotic derived from the Pseudomonas quinolone signal PQS exhibited highly potent antibiotic activity against Moraxella catarrhalis likely by inhibiting a target in the primary energy metabolism Szamosvári et al.

Consistently, cellular ATP concentrations in M. catarrhalis dropped significantly after exposure to this compound. However, the specific targets of this thiochromenone antibiotic are still unclear.

Similarly, lugdunin was reported to be related to the swift breakdown of bacterial energy resources as it ceased the incorporation of radioactive precursors of DNA, RNA, protein, and cell wall under low concentrations nearly at the meantime Zipperer et al.

It is noteworthy that lugdunin was capable of coping with a series of Gram-positive bacteria, especially the notorious methicillin-resistant S. aureus MRSA and the VRE isolates. Together, these precise antibiotics harbor few and critical sites of action that closely take part in bacterial survival and reproduction.

They can be more suitable, more efficient, and would not induce the subsequent severe infections. One of the principles of antibiotic use is the prioritization of narrow-spectrum antibiotic, especially when we have figured out the specific pathogenic bacteria.

It is good news for clinical treatment but indeed places a higher expectation on rapid diagnosis. Antimicrobial peptides AMPsalso called host-defense peptides HDPsare important components of the innate immune system Lazzaro et al. As their modes of action primarily depend on the mechanism involving electrostatic interactions between their cationic domains and negatively charged bacterial cell surface, AMPs have a lower likelihood to induce host toxicity because eukaryotic cell membrane is electrically neutral Jenssen et al.

In this regard, AMPs are not prone to induce drug resistance, thus showing broad prospects to perform as ideal antibiotic alternatives in this resistance era Liu et al. More importantly, AMPs with targeted activity turn out to be good choices for precise killing. For instance, the AMP thanatin from Podisus maculiventris was found to reverse carbapenem resistance in NDM-1—producing bacteria by dual mechanisms Ma et al.

ZY4, a cyclic peptide, not only induced membrane permeabilization in bacteria with low frequency of resistance but also showed supreme potency in coping with persister cells Mwangi et al. It had been confirmed to be able to combat with multidrug-resistant P.

aeruginosa and A. baumannii infections potently than Bacillus subtilis and S. Except membrane disruption, AMPs also play a part in several intracellular processes. In a previous work, it was reported that sublethal concentrations of P-Der from pleurocidin or frog dermaseptin could inhibit macromolecular synthesis in Escherichia coli Patrzykat et al.

Additionally, targets relevant to the formation of structural components are also worthy to be noted. For instance, a non-ribosomal lipopeptide tridecaptin A1 TriA1 produced by Bacillus and Paenibacillus species exerted antibacterial activity against Gram-negative bacteria by binding to lipid II on the inner membrane and disrupting the proton motive force Cochrane et al.

Besides, strategies based on database-filtering technology provided us inspiration to generate ideal, short, specific, and effective AMPs. For instance, the potential peptides F1 and F4 from the antimicrobial peptide database APD with an α-helical symmetrical structure displayed short, safe, and stable activity against Gram-negative pathogens such as E.

coliS. pullorumand P. aeruginosa Chou et al. However, their activities against Gram-positive bacteria were very poor as reflected in the high MIC values in S. epidermidis and P.

Until recently, although peptide antibiotics such as polymyxin B, colistin, and daptomycin have been put into clinical use for decades, doubts and criticisms constantly exist due to their incomplete success with dose-dependent toxicity and short half-life in vivo.

So, after sophisticated designing and screening, AMPs with activities still need to undergo tests in terms of protease stability and cytoxicity. In this case, structural modification such as lipophilic fatty acid chain removal Liu et al.

At the end of the lytic cycle of bacteriophages, lysins will be released and accumulated in the cytoplasm Fischetti, The nature of lysin is enzyme, which is composed of two parts: the catalytic domain in the N -terminal region and the binding domain in the C -terminal region.

The former exhibits catalytic activity, and the latter has specificity for molecules existing in the host cell wall. Considering this mode of action, we may conclude their excellent activities against Gram-positive bacteria with cell wall and the inefficiency toward Gram-negative bacteria possessing an impermeable outer membrane.

However, based on comprehensive understanding, lysins are indeed potent targeted antimicrobial agents owing to their high specificity, low frequency of resistance, and rich sources Sharma U.

et al. First and foremost, the values of lysins in infection control, especially in aquaculture and stock farming, have been partly acknowledged.

One typical example is the lysin PlyC produced by phage C1, which had distinctive and exclusive therapeutic activity against Streptococcus sp.

Likewise, Cpl-1 and Pal, lysins isolated from active bacteriophages against Streptococcus pneumoniaetargeted the same host but exhibited different catalytic activities Jado et al. It is noteworthy that this synergy mechanism indeed reduced the emergence of resistance to lysins. Additionally, working in coordination with oxacillina, the chimeric lysin Clys, synthesized by the fusion of the N -terminal domain of phage Twort lysin, and the C -terminal domain of the phage phiNM3 lysin, exhibited good protection against MRSA in in vivo models Daniel et al.

It is without doubt an imperative work as MRSA is responsible for various skin and soft-tissue infections and symptoms associated with dairy cow mastitis. Another lysin with the same target is CF, which was specialized in disrupting S.

aureus biofilms Schuch et al. The flooding of lysins is also good news for all kinds of nosocomial infections.

: Anti-infection strategies

Anti-virulence Strategies to Target Bacterial Infections | SpringerLink Vet Microbiol — Huggins, W. The antimicrobial-resistant germs survive and multiply. Bailey L, Gylfe A, Sundin C, Muschiol S, Elofsson M, Nordstrom P, Henriques-Normark B, Lugert R, Waldenstrom A, Wolf-Watz H et al Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle. These actions result in the exposure of surviving pathogens to sub-therapeutic concentrations of antimicrobials thus increasing the chances of acquiring resistance. Kulp A, Kuehn MJ Biological functions and biogenesis of secreted bacterial outer membrane vesicles.
Antimicrobial resistant bacteria - Better Health Channel This table gives a few examples Strstegies defense strategies used to Thermogenesis and cardiovascular health the effects Strattegies antibiotics Anti-infetion Foods to enhance recovery. Phage therapy to treat bacterial infections with Anti-intection bacteriophages, alone or in combination with traditional antibiotics, is a promising strategy to combat MDR infections [ 19 ]. Ma, J. One of the challenges in disrupting quorum sensing networks is the fact that a pathogen may possess several QS systems of the same class, for example P. The prime requirement for screening natural products is to identify novel chemical scaffolds sustaining antibacterial activity.
Frontiers | Targeted Therapeutic Strategies in the Battle Against Pathogenic Bacteria

Antimicrobial resistant bacteria can also be passed from person to person within the community. This is becoming more common. Ways to prevent transmission of organisms, including antibiotic resistant bacteria, are:. This page has been produced in consultation with and approved by:.

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Antimicrobial resistant bacteria. Actions for this page Listen Print. Summary Read the full fact sheet. On this page. About antimicrobial resistance Bacteria resistant to antibiotics Ways to prevent antimicrobial resistance Transmission of antimicrobial resistant bacteria in hospitals Infection prevention and control in hospitals Additional precautions with antimicrobial resistant bacteria Transmission of antimicrobial resistant bacteria in the community Where to get help.

About antimicrobial resistance Antibiotic medications are used to treat infections and diseases caused by bacteria. Bacteria resistant to antibiotics Some bacteria have developed resistance to antibiotics that were once commonly used to treat them.

Important examples of antimicrobial resistance strains of bacteria are: methicillin-resistant Staphylococcus aureus MRSA vancomycin-resistant Enterococcus VRE multi-drug-resistant Mycobacterium tuberculosis MDR-TB carbapenemase-producing Enterobacterales CPE.

Ways to prevent antimicrobial resistance The most important ways to prevent antimicrobial resistance are to: Use antibiotics appropriately. It is important to reduce unnecessary and over-prescribing of antibiotics. For example, when antibiotics are prescribed for conditions that do not require them such as viral illness antibiotics do not work against viruses.

Complete the entire course of any prescribed antibiotic so that it can be fully effective and not breed resistance. Practise good hygiene such as handwashing and use appropriate infection control procedures.

Transmission of antimicrobial resistant bacteria in hospitals The common ways in which bacteria can be passed from person to person include: contact with contaminated hands of hospital staff contact with contaminated surfaces such as door handles, over-bed tables and call bells contact with contaminated equipment, such as stethoscopes and blood pressure cuffs.

Infection prevention and control in hospitals Standard precautions in hospitals are work practices that provide a basic level of infection prevention and control for the care of all people, regardless of their diagnosis or presumed infection status.

Bacteria cause infections such as strep throat, foodborne illnesses, and other serious infections. Antibiotics treat bacterial infections. Antifungals treat fungal infections. On This Page. How Antibiotic and Antifungal Use Affects Resistance Antibiotics and antifungals save lives, but their use can contribute to the development of resistant germs.

Resistance Mechanisms Defense Strategies Resistance Mechanisms Defense Strategies Description Restrict access of the antibiotic Germs restrict access by changing the entryways or limiting the number of entryways. Get rid of the antibiotic or antifungal Germs get rid of antibiotics using pumps in their cell walls to remove antibiotic drugs that enter the cell.

Change or destroy the antibiotic Germs change or destroy the antibiotics with enzymes, proteins that break down the drug. Change the targets for the antibiotic or antifungal Many antibiotic drugs are designed to single out and destroy specific parts or targets of a bacterium.

Fact Sheets. How Resistance Spreads. Bacteria and Fungi Fight Back. How Resistance Moves Directly Germ to Germ. Select Germs Showing Resistance Over Time. Top of Page.

Last Reviewed: October 5, Source: Centers for Disease Control and Prevention , National Center for Emerging and Zoonotic Infectious Diseases NCEZID , Division of Healthcare Quality Promotion DHQP.

Facebook Twitter LinkedIn Syndicate. home Antimicrobial Resistance. To receive email updates about this page, enter your email address: Email Address. What's this? Links with this icon indicate that you are leaving the CDC website. Wright JS 3rd, Jin R, Novick RP Transient interference with staphylococcal quorum sensing blocks abscess formation.

Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny JV, Tang W, Bansal A, Cummings RT, Cunningham BR, Friedlander AM et al The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection.

Zahid MS, Awasthi SP, Asakura M, Chatterjee S, Hinenoya A, Faruque SM, Yamasaki S Suppression of virulence of toxigenic Vibrio cholerae by anethole through the cyclic AMP cAMP -cAMP receptor protein signaling system.

PLoS ONE e Zambelloni R, Marquez R, Roe AJ Development of antivirulence compounds: a biochemical review. Zetterstrom CE, Hasselgren J, Salin O, Davis RA, Quinn RJ, Sundin C, Elofsson M The resveratrol tetramer - -hopeaphenol inhibits type III secretion in the gram-negative pathogens Yersinia pseudotuber-culosis and Pseudomonas aeruginosa.

PLoS ONE 8:e Zhang C, Zhang W Escherichia coli K88ac fimbriae expressing heat-labile and heat-stable STa toxin epitopes elicit antibodies that neutralize cholera toxin and STa toxin and inhibit adherence of K88ac fimbrial E. Zhang J, Liu H, Zhu K, Gong S, Dramsi S, Wang YT, Li J, Chen F, Zhang R, Zhou L et al Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.

Download references. Work of P. Dersch is supported by the German Research Foundation and the German Center of Infection Research DZIF, TTU-GI.

Helmholtz-Zentrum für Infektionsforschung and Deutsches Zentrum für Infektionsforschung, Inhoffenstr. You can also search for this author in PubMed Google Scholar. Correspondence to Petra Dersch. Department Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Niedersachsen, Germany.

Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Niedersachsen, Germany. Reprints and permissions.

Mühlen, S. Anti-virulence Strategies to Target Bacterial Infections. In: Stadler, M. eds How to Overcome the Antibiotic Crisis. Current Topics in Microbiology and Immunology, vol Springer, Cham. Published : 05 March Publisher Name : Springer, Cham. Print ISBN : Online ISBN : eBook Packages : Biomedical and Life Sciences Biomedical and Life Sciences R0.

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Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract Resistance of important bacterial pathogens to common antimicrobial therapies and the emergence of multidrug-resistant bacteria are increasing at an alarming rate and constitute one of our greatest challenges in the combat of bacterial infection and accompanied diseases.

Keywords Secretion System Protective Antigen Shiga Toxin Lethal Factor Anthrax Toxin These keywords were added by machine and not by the authors.

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References Aarestrup FM Veterinary drug usage and antimicrobial resistance in bacteria of animal origin. Basic Clin Pharmacol Toxicol — Article CAS PubMed Google Scholar Ackermann M A functional perspective on phenotypic heterogeneity in microorganisms.

Nat Rev Microbiol — Article CAS PubMed Google Scholar Aggarwal C, Jimenez JC, Lee H, Chlipala GE, Ratia K, Federle MJ Identification of quorum-sensing inhibitors disrupting signaling between Rgg and short hydrophobic peptides in Streptococci.

MBio 6:e—e Article CAS PubMed PubMed Central Google Scholar Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J Call of the wild: antibiotic resistance genes in natural environments.

Nat Rev Microbiol — Article CAS PubMed Google Scholar Altier C, Suyemoto M, Ruiz AI, Burnham KD, Maurer R Characterization of two novel regulatory genes affecting Salmonella invasion gene expression.

Mol Microbiol — Article CAS PubMed Google Scholar Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL Human botulism immune globulin for the treatment of infant botulism. N Engl J Med — Article CAS PubMed Google Scholar Arya R, Princy SA An insight into pleiotropic regulators Agr and Sar: molecular probes paving the new way for antivirulent therapy.

Future Microbiol — Article CAS PubMed Google Scholar Avery SV Microbial cell individuality and the underlying sources of heterogeneity. Nat Rev Microbiol — Article CAS PubMed Google Scholar Bailey L, Gylfe A, Sundin C, Muschiol S, Elofsson M, Nordstrom P, Henriques-Normark B, Lugert R, Waldenstrom A, Wolf-Watz H et al Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle.

FEBS Lett — Article CAS PubMed Google Scholar Baldari CT, Tonello F, Paccani SR, Montecucco C Anthrax toxins: a paradigm of bacterial immune suppression.

Trends Immunol — Article CAS PubMed Google Scholar Bannwarth L, Goldberg AB, Chen C, Turk BE Identification of exosite-targeting inhibitors of anthrax lethal factor by high-throughput screening. Chem Biol — Article CAS PubMed PubMed Central Google Scholar Barnhart MM, Sauer FG, Pinkner JS, Hultgren SJ Chaperone-subunit-usher interactions required for donor strand exchange during bacterial pilus assembly.

J Bacteriol — Article CAS PubMed PubMed Central Google Scholar Baron C Antivirulence drugs to target bacterial secretion systems. Curr Opin Microbiol — Article CAS PubMed Google Scholar Barraud N, Hassett DJ, Hwang SH, Rice SA, Kjelleberg S, Webb JS Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa.

J Bacteriol — Article CAS PubMed PubMed Central Google Scholar Barraud N, Schleheck D, Klebensberger J, Webb JS, Hassett DJ, Rice SA, Kjelleberg S Nitric oxide signaling in Pseudomonas aeruginosa biofilms mediates phosphodiesterase activity, decreased cyclic di-GMP levels, and enhanced dispersal.

J Bacteriol — Article CAS PubMed PubMed Central Google Scholar Basha S, Rai P, Poon V, Saraph A, Gujraty K, Go MY, Sadacharan S, Frost M, Mogridge J, Kane RS Polyvalent inhibitors of anthrax toxin that target host receptors.

Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Beckham KS, Roe AJ From screen to target: insights and approaches for the development of anti-virulence compounds. Front Cell Infect Microbiol Article PubMed PubMed Central CAS Google Scholar Berendonk TU, Manaia CM, Merlin C, Fatta-Kassinos D, Cytryn E, Walsh F, Burgmann H, Sorum H, Norstrom M, Pons MN et al Tackling antibiotic resistance: the environmental framework.

Nat Rev Microbiol — Article CAS PubMed Google Scholar Bierne H, Mazmanian SK, Trost M, Pucciarelli MG, Liu G, Dehoux P, Jansch L, Garcia-del Portillo F, Schneewind O, Cossart P et al Inactivation of the srtA gene in Listeria monocytogenes inhibits anchoring of surface proteins and affects virulence.

Mol Microbiol — Article CAS PubMed Google Scholar Bliska JB, Wang X, Viboud GI, Brodsky IE Modulation of innate immune responses by Yersinia type III secretion system translocators and effectors. Cell Microbiol — CAS PubMed PubMed Central Google Scholar Blizzard TA, Chen H, Kim S, Wu J, Bodner R, Gude C, Imbriglio J, Young K, Park YW, Ogawa A et al Discovery of MK, a beta-lactamase inhibitor for combination with Primaxin R.

Bioorg Med Chem Lett — Article CAS PubMed Google Scholar Böhme K, Steinmann R, Kortmann J, Seekircher S, Heroven AK, Berger E, Pisano F, Thiermann T, Wolf-Watz H, Narberhaus F et al Concerted actions of a thermo-labile regulator and a unique intergenic RNA thermosensor control Yersinia virulence.

PLoS Pathog 8:e Article PubMed PubMed Central CAS Google Scholar Bohnert JA, Kern WV Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother — Article CAS PubMed PubMed Central Google Scholar Bowser TE, Bartlett VJ, Grier MC, Verma AK, Warchol T, Levy SB, Alekshun MN Novel anti-infection agents: small-molecule inhibitors of bacterial transcription factors.

Bioorg Med Chem Lett — Article CAS PubMed Google Scholar Boyd B, Lingwood C Verotoxin receptor glycolipid in human renal tissue. Nephron — Article CAS PubMed Google Scholar Brautaset T, Lale R, Valla S Positively regulated bacterial expression systems. Microb Biotechnol —30 Article CAS PubMed Google Scholar Brown HL, Hanman K, Reuter M, Betts RP, van Vliet AH Campylobacter jejuni biofilms contain extracellular DNA and are sensitive to DNase I treatment.

Front Microbiol Article PubMed PubMed Central Google Scholar Bruckner R, Titgemeyer F Carbon catabolite repression in bacteria: choice of the carbon source and autoregulatory limitation of sugar utilization. FEMS Microbiol Lett — Article CAS PubMed Google Scholar Burton NA, Schurmann N, Casse O, Steeb AK, Claudi B, Zankl J, Schmidt A, Bumann D Disparate impact of oxidative host defenses determines the fate of Salmonella during systemic infection in mice.

Cell Host Microbe —83 Article CAS PubMed Google Scholar Canton R Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting.

Clin Microbiol Infect 15 Suppl 1 —25 Article CAS PubMed Google Scholar Carlier M, Carrette S, Stove V, Verstraete AG, De Waele JJ Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients?

Int J Antimicrob Agents — Article CAS PubMed Google Scholar Cascioferro S, Totsika M, Schillaci D Sortase A: an ideal target for anti-virulence drug development. Microb Pathog — Article CAS PubMed Google Scholar Cascioferro S, Raffa D, Maggio B, Raimondi MV, Schillaci D, Daidone G Sortase A inhibitors: recent advances and future perspectives.

J Med Chem Google Scholar Castanheira M, Williams G, Jones RN, Sader HS Activity of ceftaroline-avibactam tested against contemporary Enterobacteriaceae isolates carrying beta-lactamases prevalent in the United States.

Microb Drug Resist — Article CAS PubMed Google Scholar Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ The biology and future prospects of antivirulence therapies. Nat Rev Microbiol —27 Article CAS PubMed PubMed Central Google Scholar Chan AH, Wereszczynski J, Amer BR, Yi SW, Jung ME, McCammon JA, Clubb RT Discovery of Staphylococcus aureus sortase A inhibitors using virtual screening and the relaxed complex scheme.

Chem Biol Drug Des — Article CAS PubMed Google Scholar Chandran V Type IV secretion machinery: molecular architecture and function.

Biochem Soc Trans —28 Article CAS PubMed Google Scholar Chao Y, Vogel J The role of Hfq in bacterial pathogens. Curr Opin Microbiol —33 Article CAS PubMed Google Scholar Chaudhuri RR, Morgan E, Peters SE, Pleasance SJ, Hudson DL, Davies HM, Wang J, van Diemen PM, Buckley AM, Bowen AJ et al Comprehensive assignment of roles for Salmonella typhimurium genes in intestinal colonization of food-producing animals.

PLoS Genet 9:e Article CAS PubMed PubMed Central Google Scholar Chen Z, Moayeri M, Purcell R Monoclonal antibody therapies against anthrax.

Toxins Basel — Article CAS Google Scholar Chhabra SR, Stead P, Bainton NJ, Salmond GP, Stewart GS, Williams P, Bycroft BW Autoregulation of carbapenem biosynthesis in Erwinia carotovora by analogues of N- 3-oxohexanoyl -L-homoserine lactone.

J Antibiot Tokyo — Article CAS Google Scholar Clarke DJ The Rcs phosphorelay: more than just a two-component pathway. Future Microbiol — Article CAS PubMed Google Scholar Clatworthy AE, Pierson E, Hung DT Targeting virulence: a new paradigm for antimicrobial therapy.

Nat Chem Biol — Article CAS PubMed Google Scholar Claudi B, Sprote P, Chirkova A, Personnic N, Zankl J, Schurmann N, Schmidt A, Bumann D Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy.

Cell — Article CAS PubMed Google Scholar Coban AY, Tanriverdi Cayci Y, Erturan Z, Durupinar B Effects of efflux pump inhibitors phenyl-arginine-beta-naphthylamide and 1- 1-naphthylmethyl -piperazine on the antimicrobial susceptibility of Pseudomonas aeruginosa isolates from cystic fibrosis patients.

J Chemother — Article CAS PubMed Google Scholar Coburn B, Sekirov I, Finlay BB Type III secretion systems and disease. Clin Microbiol Rev — Article CAS PubMed PubMed Central Google Scholar Coleman K, Levasseur P, Girard AM, Borgonovi M, Miossec C, Merdjan H, Drusano G, Shlaes D, Nichols WW Activities of ceftazidime and avibactam against beta-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model.

Antimicrob Agents Chemother — Article PubMed PubMed Central CAS Google Scholar Conover MS, Mishra M, Deora R Extracellular DNA is essential for maintaining Bordetella biofilm integrity on abiotic surfaces and in the upper respiratory tract of mice.

PLoS ONE 6:e Article CAS PubMed PubMed Central Google Scholar Control CfD Antibiotic resistance threats in the United States Google Scholar Costerton JW, Stewart PS, Greenberg EP Bacterial biofilms: a common cause of persistent infections.

Science — Article CAS PubMed Google Scholar Cryan LM, Rogers MS Targeting the anthrax receptors, TEM-8 and CMG-2, for anti-angiogenic therapy. Front Biosci Landmark Ed — Article CAS Google Scholar Cryan LM, Habeshian KA, Caldwell TP, Morris MT, Ackroyd PC, Christensen KA, Rogers MS Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay.

J Biomol Screen — Article PubMed CAS Google Scholar Curtis MM, Russell R, Moreira CG, Adebesin AM, Wang C, Williams NS, Taussig R, Stewart D, Zimmern P, Lu B et al QseC inhibitors as an antivirulence approach for Gram-negative pathogens.

Science — Article PubMed Google Scholar Deep A, Chaudhary U, Gupta V Quorum sensing and bacterial pathogenicity: from molecules to disease.

EMBO Rep — Article PubMed PubMed Central CAS Google Scholar Desroy N, Denis A, Oliveira C, Atamanyuk D, Briet S, Faivre F, LeFralliec G, Bonvin Y, Oxoby M, Escaich S et al Novel HldE-K inhibitors leading to attenuated Gram negative bacterial virulence.

J Med Chem — Article CAS PubMed Google Scholar Deutscher J, Herro R, Bourand A, Mijakovic I, Poncet S P-Ser-HPr—a link between carbon metabolism and the virulence of some pathogenic bacteria. Biochim Biophys Acta — Article CAS PubMed Google Scholar Diard M, Garcia V, Maier L, Remus-Emsermann MN, Regoes RR, Ackermann M, Hardt WD Stabilization of cooperative virulence by the expression of an avirulent phenotype.

Nature — Article CAS PubMed Google Scholar Dong YH, Xu JL, Li XZ, Zhang LH AiiA, an enzyme that inactivates the acylhomoserine lactone quorum-sensing signal and attenuates the virulence of Erwinia carotovora.

Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Dong YH, Wang LH, Xu JL, Zhang HB, Zhang XF, Zhang LH Quenching quorum-sensing-dependent bacterial infection by an N-acyl homoserine lactonase.

Nature — Article CAS PubMed Google Scholar Dong YH, Gusti AR, Zhang Q, Xu JL, Zhang LH Identification of quorum-quenching N-acyl homoserine lactonases from Bacillus species.

Appl Environ Microbiol — Article CAS PubMed PubMed Central Google Scholar Duncan MC, Wong WR, Dupzyk AJ, Bray WM, Linington RG, Auerbuch V An NF-kappaB-based high-throughput screen identifies piericidins as inhibitors of the Yersinia pseudotuberculosis type III secretion system.

Antimicrob Agents Chemother — Article PubMed PubMed Central CAS Google Scholar Duss O, Michel E, Yulikov M, Schubert M, Jeschke G, Allain FH Structural basis of the non-coding RNA RsmZ acting as a protein sponge.

Nature — Article CAS PubMed Google Scholar Escaich S Antivirulence as a new antibacterial approach for chemotherapy. Curr Opin Chem Biol — Article CAS PubMed Google Scholar Escaich S Novel agents to inhibit microbial virulence and pathogenicity.

Expert Opin Ther Pat — Article CAS PubMed Google Scholar Felise HB, Nguyen HV, Pfuetzner RA, Barry KC, Jackson SR, Blanc MP, Bronstein PA, Kline T, Miller SI An inhibitor of gram-negative bacterial virulence protein secretion.

Cell Host Microbe — Article CAS PubMed PubMed Central Google Scholar Feng L, Rutherford ST, Papenfort K, Bagert JD, van Kessel JC, Tirrell DA, Wingreen NS, Bassler BL A qrr noncoding RNA deploys four different regulatory mechanisms to optimize quorum-sensing dynamics.

Cell — Article CAS PubMed PubMed Central Google Scholar Fernicola S, Paiardini A, Giardina G, Rampioni G, Leoni L, Cutruzzola F, Rinaldo S In silico discovery and in vitro validation of catechol-containing sulfonohydrazide compounds as potent inhibitors of the diguanylate cyclase PleD.

J Bacteriol Google Scholar Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LE Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis.

Nat Chem Biol —32 Article CAS PubMed Google Scholar Field M Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest — Article CAS PubMed PubMed Central Google Scholar Firon N, Ashkenazi S, Mirelman D, Ofek I, Sharon N Aromatic alpha-glycosides of mannose are powerful inhibitors of the adherence of type 1 fimbriated Escherichia coli to yeast and intestinal epithelial cells.

Infect Immun — CAS PubMed PubMed Central Google Scholar Forst SA, Roberts DL Signal transduction by the EnvZ-OmpR phosphotransfer system in bacteria.

Res Microbiol — Article CAS PubMed Google Scholar Francois B, Luyt CE, Dugard A, Wolff M, Diehl JL, Jaber S, Forel JM, Garot D, Kipnis E, Mebazaa A et al Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized, double-blind, placebo-controlled trial.

Crit Care Med — Article CAS PubMed Google Scholar Galan JE, Wolf-Watz H Protein delivery into eukaryotic cells by type III secretion machines. Nature — Article CAS PubMed Google Scholar Garrity-Ryan LK, Kim OK, Balada-Llasat JM, Bartlett VJ, Verma AK, Fisher ML, Castillo C, Songsungthong W, Tanaka SK, Levy SB et al Small molecule inhibitors of LcrF, a Yersinia pseudotuberculosis transcription factor, attenuate virulence and limit infection in a murine pneumonia model.

BMC Pharmacol Article PubMed PubMed Central CAS Google Scholar Greener M How Escherichia coli kills. Mol Med Today Article CAS PubMed Google Scholar Groisman EA, Mouslim C Sensing by bacterial regulatory systems in host and non-host environments.

Nat Rev Microbiol — Article CAS PubMed Google Scholar Gu J, Ning Y, Wang H, Xiao D, Tang B, Luo P, Cheng Y, Jiang M, Li N, Zou Q et al Vaccination of attenuated EIS-producing Salmonella induces protective immunity against enterohemorrhagic Escherichia coli in mice.

Vaccine — Article CAS PubMed Google Scholar Hall-Stoodley L, Costerton JW, Stoodley P Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol — Article CAS PubMed Google Scholar Han Z, Pinkner JS, Ford B, Obermann R, Nolan W, Wildman SA, Hobbs D, Ellenberger T, Cusumano CK, Hultgren SJ et al Structure-based drug design and optimization of mannoside bacterial FimH antagonists.

J Med Chem — Article CAS PubMed PubMed Central Google Scholar Han Z, Pinkner JS, Ford B, Chorell E, Crowley JM, Cusumano CK, Campbell S, Henderson JP, Hultgren SJ, Janetka JW Lead optimization studies on FimH antagonists: discovery of potent and orally bio-available ortho-substituted biphenyl mannosides.

J Med Chem — Article CAS PubMed PubMed Central Google Scholar Harmon DE, Davis AJ, Castillo C, Mecsas J Identification and characterization of small-molecule inhibitors of Yop translocation in Yersinia pseudotuberculosis. Antimicrob Agents Chemother — Article CAS PubMed PubMed Central Google Scholar Harmsen M, Lappann M, Knochel S, Molin S Role of extracellular DNA during biofilm formation by Listeria monocytogenes.

Appl Environ Microbiol — Article CAS PubMed PubMed Central Google Scholar Hartmann M, Papavlassopoulos H, Chandrasekaran V, Grabosch C, Beiroth F, Lindhorst TK, Rohl C Inhibition of bacterial adhesion to live human cells: activity and cytotoxicity of synthetic mannosides.

FEBS Lett — Article CAS PubMed Google Scholar Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA, Holden DW Internalization of Salmonella by macrophages induces formation of nonreplicating persisters.

Science — Article CAS PubMed Google Scholar Henkel JS, Baldwin MR, Barbieri JT Toxins from bacteria. EXS —29 CAS PubMed PubMed Central Google Scholar Hentzer M, Givskov M Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections.

J Clin Invest — Article CAS PubMed PubMed Central Google Scholar Hentzer M, Riedel K, Rasmussen TB, Heydorn A, Andersen JB, Parsek MR, Rice SA, Eberl L, Molin S, Hoiby N et al Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound.

RNA Biol — Article CAS PubMed Google Scholar Hesterkamp T Antibiotics clinical development and pipeline. Curr Top Microbiol Immunol Google Scholar Hilleringmann M, Pansegrau W, Doyle M, Kaufman S, MacKichan ML, Gianfaldoni C, Ruggiero P, Covacci A Inhibitors of Helicobacter pylori ATPase Cagalpha block CagA transport and cag virulence.

Microbiology — Article CAS PubMed Google Scholar Hopwood DA How do antibiotic-producing bacteria ensure their self-resistance before antibiotic biosynthesis incapacitates them? Mol Microbiol — Article CAS PubMed Google Scholar Hudson DL, Layton AN, Field TR, Bowen AJ, Wolf-Watz H, Elofsson M, Stevens MP, Galyov EE Inhibition of type III secretion in Salmonella enterica serovar Typhimurium by small-molecule inhibitors.

Antimicrob Agents Chemother — Article CAS PubMed PubMed Central Google Scholar Hueck CJ Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol Mol Biol Rev — CAS PubMed PubMed Central Google Scholar Hung DT, Shakhnovich EA, Pierson E, Mekalanos JJ Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization.

Science — Article CAS PubMed Google Scholar Iwatsuki M, Uchida R, Yoshijima H, Ui H, Shiomi K, Kim YP, Hirose T, Sunazuka T, Abe A, Tomoda H et al Guadinomines, type III secretion system inhibitors, produced by Streptomyces sp.

J Antibiot Tokyo — Article CAS Google Scholar Izano EA, Amarante MA, Kher WB, Kaplan JB Differential roles of poly-N-acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl Environ Microbiol — Article CAS PubMed Google Scholar Izore T, Job V, Dessen A Biogenesis, regulation, and targeting of the type III secretion system.

Structure — Article CAS PubMed Google Scholar Jeon B, Zhang Q Sensitization of Campylobacter jejuni to fluoroquinolone and macrolide antibiotics by antisense inhibition of the CmeABC multidrug efflux transporter. J Antimicrob Chemother — Article CAS PubMed PubMed Central Google Scholar Johansson J, Mandin P, Renzoni A, Chiaruttini C, Springer M, Cossart P An RNA thermosensor controls expression of virulence genes in Listeria monocytogenes.

Cell — Article PubMed Google Scholar Jonsson IM, Mazmanian SK, Schneewind O, Verdrengh M, Bremell T, Tarkowski A On the role of Staphylococcus aureus sortase and sortase-catalyzed surface protein anchoring in murine septic arthritis.

J Infect Dis — Article CAS PubMed Google Scholar Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, Khan IA Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus.

J Antimicrob Chemother — Article CAS PubMed Google Scholar Kaplan BS, Meyers KE, Schulman SL The pathogenesis and treatment of hemolytic uremic syndrome.

J Am Soc Nephrol — CAS PubMed Google Scholar Kaplan JB, Velliyagounder K, Ragunath C, Rohde H, Mack D, Knobloch JK, Ramasubbu N Genes involved in the synthesis and degradation of matrix polysaccharide in Actinobacillus actinomycetemcomitans and Actinobacillus pleuropneumoniae biofilms.

J Bacteriol — Article CAS PubMed PubMed Central Google Scholar Karginov VA, Yohannes A, Robinson TM, Fahmi NE, Alibek K, Hecht SM Beta-cyclodextrin derivatives that inhibit anthrax lethal toxin.

Bioorg Med Chem —40 Article CAS PubMed Google Scholar Kauppi AM, Nordfelth R, Uvell H, Wolf-Watz H, Elofsson M Targeting bacterial virulence: inhibitors of type III secretion in Yersinia.

Chem Biol — Article CAS PubMed Google Scholar Kern WV, Steinke P, Schumacher A, Schuster S, von Baum H, Bohnert JA Effect of 1- 1-naphthylmethyl -piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli.

J Antimicrob Chemother — Article CAS PubMed Google Scholar Keyser P, Elofsson M, Rosell S, Wolf-Watz H Virulence blockers as alternatives to antibiotics: type III secretion inhibitors against Gram-negative bacteria. J Intern Med —29 Article CAS PubMed Google Scholar Kim OK, Garrity-Ryan LK, Bartlett VJ, Grier MC, Verma AK, Medjanis G, Donatelli JE, Macone AB, Tanaka SK, Levy SB et al N-hydroxybenzimidazole inhibitors of the transcription factor LcrF in Yersinia : novel antivirulence agents.

J Med Chem — Article CAS PubMed PubMed Central Google Scholar Kim S, Jiao GS, Moayeri M, Crown D, Cregar-Hernandez L, McKasson L, Margosiak SA, Leppla SH, Johnson AT Antidotes to anthrax lethal factor intoxication. Bioorg Med Chem Lett — Article CAS PubMed PubMed Central Google Scholar Kimura K, Iwatsuki M, Nagai T, Matsumoto A, Takahashi Y, Shiomi K, Omura S, Abe A A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium.

J Antibiot Tokyo — Article CAS Google Scholar Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature — Article CAS PubMed Google Scholar Klein T, Abgottspon D, Wittwer M, Rabbani S, Herold J, Jiang X, Kleeb S, Luthi C, Scharenberg M, Bezencon J et al FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation.

J Med Chem — Article CAS PubMed Google Scholar Kline T, Bowman J, Iglewski BH, de Kievit T, Kakai Y, Passador L Novel synthetic analogs of the Pseudomonas autoinducer.

Bioorg Med Chem Lett — Article CAS PubMed Google Scholar Kolodkin-Gal I, Romero D, Cao S, Clardy J, Kolter R, Losick R D-amino acids trigger biofilm disassembly.

Science — Article CAS PubMed PubMed Central Google Scholar Kolodkin-Gal I, Cao S, Chai L, Bottcher T, Kolter R, Clardy J, Losick R A self-produced trigger for biofilm disassembly that targets exopolysaccharide.

Cell — Article CAS PubMed PubMed Central Google Scholar Kong KF, Schneper L, Mathee K Beta-lactam antibiotics: from antibiosis to resistance and bacteriology. APMIS —36 Article CAS PubMed PubMed Central Google Scholar Koppolu V, Osaka I, Skredenske JM, Kettle B, Hefty PS, Li J, Egan SM Small-molecule inhibitor of the Shigella flexneri master virulence regulator VirF.

Infect Immun — Article CAS PubMed PubMed Central Google Scholar Kortmann J, Narberhaus F Bacterial RNA thermometers: molecular zippers and switches.

Nat Rev Microbiol — Article CAS PubMed Google Scholar Krachler AM, Orth K Targeting the bacteria-host interface: strategies in anti-adhesion therapy. Virulence — Article PubMed PubMed Central Google Scholar Kulkarni AA, Fuller C, Korman H, Weiss AA, Iyer SS Glycan encapsulated gold nanoparticles selectively inhibit shiga toxins 1 and 2.

Bioconjug Chem — Article CAS PubMed PubMed Central Google Scholar Kulp A, Kuehn MJ Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu Rev Microbiol — Article CAS PubMed PubMed Central Google Scholar Kunsmann L, Ruter C, Bauwens A, Greune L, Gluder M, Kemper B, Fruth A, Wai SN, He X, Lloubes R et al Virulence from vesicles: novel mechanisms of host cell injury by Escherichia coli O H4 outbreak strain.

Sci Rep Article CAS PubMed PubMed Central Google Scholar Kuzmic P, Cregar L, Millis SZ, Goldman M Mixed-type noncompetitive inhibition of anthrax lethal factor protease by aminoglycosides.

FEBS J — Article CAS PubMed Google Scholar Langridge GC, Phan MD, Turner DJ, Perkins TT, Parts L, Haase J, Charles I, Maskell DJ, Peters SE, Dougan G et al Simultaneous assay of every Salmonella Typhi gene using one million transposon mutants.

Genome Res — Article CAS PubMed PubMed Central Google Scholar LaSarre B, Federle MJ Exploiting quorum sensing to confuse bacterial pathogens. Microbiol Mol Biol Rev — Article CAS PubMed PubMed Central Google Scholar Layton AN, Hudson DL, Thompson A, Hinton JC, Stevens JM, Galyov EE, Stevens MP Salicylidene acylhydrazide-mediated inhibition of type III secretion system-1 in Salmonella enterica serovar Typhimurium is associated with iron restriction and can be reversed by free iron.

Infect Immun — CAS PubMed PubMed Central Google Scholar Lewis K Persister cells and the riddle of biofilm survival. Biochemistry Mosc — Article CAS Google Scholar Lewis K Multidrug tolerance of biofilms and persister cells.

Curr Top Microbiol Immunol — CAS PubMed Google Scholar Li H, Qian L, Chen Z, Thibault D, Liu G, Liu T, Thanassi DG The outer membrane usher forms a twin-pore secretion complex. J Mol Biol — Article CAS PubMed Google Scholar Linden SK, Sheng YH, Every AL, Miles KM, Skoog EC, Florin TH, Sutton P, McGuckin MA MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy.

PLoS Pathog 5:e Article PubMed PubMed Central CAS Google Scholar Linington RG, Robertson M, Gauthier A, Finlay BB, van Soest R, Andersen RJ Caminoside A, an antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia.

Org Lett — Article CAS PubMed Google Scholar Loh E, Kugelberg E, Tracy A, Zhang Q, Gollan B, Ewles H, Chalmers R, Pelicic V, Tang CM Temperature triggers immune evasion by Neisseria meningitidis.

Nature — Article CAS PubMed Google Scholar Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T et al Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa : novel agents for combination therapy.

Antimicrob Agents Chemother — Article CAS PubMed PubMed Central Google Scholar Lu TK, Collins JJ Dispersing biofilms with engineered enzymatic bacteriophage. Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Lu C, Maurer CK, Kirsch B, Steinbach A, Hartmann RW a Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa : an in vivo potent antivirulence agent targeting pqs quorum sensing.

Angew Chem Int Ed Engl — Article CAS PubMed Google Scholar Lu C, Kirsch B, Maurer CK, de Jong JC, Braunshausen A, Steinbach A, Hartmann RW b Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.

Eur J Med Chem — Article CAS PubMed Google Scholar Lucchetti-Miganeh C, Burrowes E, Baysse C, Ermel G The post-transcriptional regulator CsrA plays a central role in the adaptation of bacterial pathogens to different stages of infection in animal hosts.

Microbiology —29 Article CAS PubMed Google Scholar Lynch SV, Wiener-Kronish JP Novel strategies to combat bacterial virulence. Curr Opin Crit Care — Article PubMed PubMed Central Google Scholar Ma JK, Hunjan M, Smith R, Lehner T Specificity of monoclonal antibodies in local passive immunization against Streptococcus mutans.

Clin Exp Immunol — CAS PubMed PubMed Central Google Scholar Madsen JS, Burmolle M, Hansen LH, Sorensen SJ The interconnection between biofilm formation and horizontal gene transfer. FEMS Immunol Med Microbiol — Article CAS PubMed Google Scholar Manefield M, de Nys R, Kumar N, Read R, Givskov M, Steinberg P, Kjelleberg S Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone AHL -mediated gene expression by displacing the AHL signal from its receptor protein.

Microbiology 2 — Article CAS PubMed Google Scholar Manina G, Dhar N, McKinney JD Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe —46 Article CAS PubMed Google Scholar Maresso AW, Wu R, Kern JW, Zhang R, Janik D, Missiakas DM, Duban ME, Joachimiak A, Schneewind O Activation of inhibitors by sortase triggers irreversible modification of the active site.

Postgrad Med J — Article CAS PubMed PubMed Central Google Scholar Marshall NC, Finlay BB Targeting the type III secretion system to treat bacterial infections. Expert Opin Ther Targets — Article CAS PubMed Google Scholar Martinez JL, Fajardo A, Garmendia L, Hernandez A, Linares JF, Martinez-Solano L, Sanchez MB A global view of antibiotic resistance.

FEMS Microbiol Rev —65 Article CAS PubMed Google Scholar McHugh SM, Hill AD, Humphreys H Preventing healthcare-associated infection through education: have surgeons been overlooked?

Surgeon — Article PubMed Google Scholar McShan AC, De Guzman RN The bacterial type III secretion system as a target for developing new antibiotics.

Chem Biol Drug Des —42 Article CAS PubMed Google Scholar Mellin JR, Tiensuu T, Becavin C, Gouin E, Johansson J, Cossart P A riboswitch-regulated antisense RNA in Listeria monocytogenes.

Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Mellin JR, Koutero M, Dar D, Nahori MA, Sorek R, Cossart P Riboswitches.

Science — Article CAS PubMed Google Scholar Miethke M, Marahiel MA Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev — Article CAS PubMed PubMed Central Google Scholar Montecucco C, Tonello F, Zanotti G Stop the killer: how to inhibit the anthrax lethal factor metalloprotease.

Trends Biochem Sci — Article CAS PubMed Google Scholar Mu Y, Shen Z, Jeon B, Dai L, Zhang Q Synergistic effects of anti-CmeA and anti-CmeB peptide nucleic acids on sensitizing Campylobacter jejuni to antibiotics.

Antimicrob Agents Chemother — Article CAS PubMed PubMed Central Google Scholar Muschiol S, Bailey L, Gylfe A, Sundin C, Hultenby K, Bergstrom S, Elofsson M, Wolf-Watz H, Normark S, Henriques-Normark B A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis.

Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Nagai H, Kubori T Type IVB secretion systems of Legionella and other Gram-negative bacteria.

Front Microbiol Article PubMed PubMed Central Google Scholar Negrea A, Bjur E, Ygberg SE, Elofsson M, Wolf-Watz H, Rhen M Salicylidene acylhydrazides that affect type III protein secretion in Salmonella enterica serovar typhimurium.

J Med Chem — Article CAS PubMed PubMed Central Google Scholar Nestorovich EM, Bezrukov SM Designing inhibitors of anthrax toxin.

Expert Opin Drug Discov — Article CAS PubMed PubMed Central Google Scholar Ng WL, Bassler BL Bacterial quorum-sensing network architectures. Annu Rev Genet — Article CAS PubMed PubMed Central Google Scholar Nikaido H, Pages JM Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria.

FEMS Microbiol Rev — Article CAS PubMed Google Scholar Nishikawa K, Matsuoka K, Watanabe M, Igai K, Hino K, Hatano K, Yamada A, Abe N, Terunuma D, Kuzuhara H et al Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation.

J Infect Dis — Article CAS PubMed Google Scholar Nordfelth R, Kauppi AM, Norberg HA, Wolf-Watz H, Elofsson M Small-molecule inhibitors specifically targeting type III secretion. Infect Immun — Article CAS PubMed PubMed Central Google Scholar Nuss AM, Heroven AK, Waldmann B, Reinkensmeier J, Jarek M, Beckstette M, Dersch P Trans-criptomic profiling of Yersinia pseudotuberculosis reveals reprogramming of the Crp regulon by temperature and uncovers Crp as a master regulator of small RNAs.

Angew Chem Int Ed Engl — Article PubMed CAS Google Scholar Ofek I, Hasty DL, Sharon N Anti-adhesion therapy of bacterial diseases: prospects and problems.

FEMS Immunol Med Microbiol — Article CAS PubMed Google Scholar Okshevsky M, Regina VR, Meyer RL Extracellular DNA as a target for biofilm control.

FEMS Microbiol Rev — Article PubMed Google Scholar Palzkill T Metallo-beta-lactamase structure and function. Ann N Y Acad Sci — Article CAS PubMed Google Scholar Pan NJ, Brady MJ, Leong JM, Goguen JD Targeting type III secretion in Yersinia pestis.

Antimicrob Agents Chemother — Article CAS PubMed Google Scholar Panchal RG, Hermone AR, Nguyen TL, Wong TY, Schwarzenbacher R, Schmidt J, Lane D, McGrath C, Turk BE, Burnett J et al Identification of small molecule inhibitors of anthrax lethal factor.

Nat Struct Mol Biol —72 Article CAS PubMed Google Scholar Pannek S, Higgins PG, Steinke P, Jonas D, Akova M, Bohnert JA, Seifert H, Kern WV Multidrug efflux inhibition in Acinetobacter baumannii : comparison between 1- 1-naphthylmethyl -piperazine and phenyl-arginine-beta-naphthylamide.

J Antimicrob Chemother — Article CAS PubMed Google Scholar Papenfort K, Vogel J Small RNA functions in carbon metabolism and virulence of enteric pathogens. Front Cell Infect Microbiol Article PubMed PubMed Central CAS Google Scholar Park S, Kim HS, Ok K, Kim Y, Park HD, Byun Y Design, synthesis and biological evaluation of 4- alkyloxy methyl-2H-pyranone derivatives as quorum sensing inhibitors.

Bioorg Med Chem Lett — Article CAS PubMed Google Scholar Parker P, Sando L, Pearson R, Kongsuwan K, Tellam RL, Smith S Bovine Muc1 inhibits binding of enteric bacteria to Caco-2 cells. Glycoconj J —97 Article CAS PubMed Google Scholar Parsek MR, Val DL, Hanzelka BL, Cronan JE Jr, Greenberg EP Acyl homoserine-lactone quorum-sensing signal generation.

Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Paschos A, den Hartigh A, Smith MA, Atluri VL, Sivanesan D, Tsolis RM, Baron C An in vivo high-throughput screening approach targeting the type IV secretion system component VirB8 identified inhibitors of Brucella abortus proliferation.

Infect Immun — Article CAS PubMed Google Scholar Paulasova P, Pellestor F The peptide nucleic acids PNAs : a new generation of probes for genetic and cytogenetic analyses. Ann Genet — Article PubMed Google Scholar Pearson JS, Zhang Y, Newton HJ, Hartland EL Post-modern pathogens: surprising activities of translocated effectors from E.

Curr Opin Microbiol —79 Article CAS PubMed Google Scholar Peschel A, Otto M, Jack RW, Kalbacher H, Jung G, Gotz F Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides.

J Biol Chem — Article CAS PubMed Google Scholar Peselis A, Serganov A Themes and variations in riboswitch structure and function.

Biochim Biophys Acta — Article CAS PubMed PubMed Central Google Scholar Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V, Pemberton N, Hedenstrom M, Larsson A, Seed P, Waksman G et al Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci USA — Article CAS PubMed PubMed Central Google Scholar Putrins M, Kogermann K, Lukk E, Lippus M, Varik V, Tenson T Phenotypic heterogeneity enables uropathogenic Escherichia coli to evade killing by antibiotics and serum complement.

Infect Immun — Article PubMed PubMed Central CAS Google Scholar Qin Z, Ou Y, Yang L, Zhu Y, Tolker-Nielsen T, Molin S, Qu D Role of autolysin-mediated DNA release in biofilm formation of Staphylococcus epidermidis. Microbiology — Article CAS PubMed Google Scholar Rasko DA, Sperandio V Anti-virulence strategies to combat bacteria-mediated disease.

Nat Rev Drug Discov — Article CAS PubMed Google Scholar Rasko DA, Moreira CG, de Li R, Reading NC, Ritchie JM, Waldor MK, Williams N, Taussig R, Wei S, Roth M et al Targeting QseC signaling and virulence for antibiotic development.

Science — Article CAS PubMed PubMed Central Google Scholar Renau TE, Leger R, Flamme EM, Sangalang J, She MW, Yen R, Gannon CL, Griffith D, Chamberland S, Lomovskaya O et al Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin.

J Med Chem — Article CAS PubMed Google Scholar Rice LB Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis — Article PubMed Google Scholar Rogers MS, Cryan LM, Habeshian KA, Bazinet L, Caldwell TP, Ackroyd PC, Christensen KA A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

Environ Microbiol — Article CAS PubMed Google Scholar Romling U, Balsalobre C Biofilm infections, their resilience to therapy and innovative treatment strategies.

Antimicrobial Foods to enhance recovery Anti-ijfection one Resveratrol and diabetes the major atrategies facing Foods to enhance recovery Energy balance diet the Twenty-First century. The spread of resistant pathogens has been such that the possibility of Anti-infecgion to a pre-antibiotic era is strxtegies. In this scenario, Foods to enhance recovery therapeutic strategies must be employed to restrict resistance. Among the innovative proposed strategies, anti-virulence therapy has been envisioned as a promising alternative for effective control of the emergence and spread of resistant pathogens. This review presents some of the anti-virulence strategies that are currently being developed, it will cover strategies focused on quench pathogen quorum sensing QS systems, disassemble of bacterial functional membrane microdomains FMMsdisruption of biofilm formation and bacterial toxin neutralization.

Anti-infection strategies -

This enzyme catalyzes the formation of the 2-aminobenzoylacetyl-CoA by the condensation of anthraniloyl-CoA with malonyl-CoA via a tetrahedral transition state. The treatment of P. aeruginosa PA14 with the potent PqsD inhibitor 2-nitrophenyl phenyl methanol disturbed the production of HHQ and PQS as well as reducing the biofilm volume Storz et al.

Moreover, some catechol-derivative compounds that act as PqsD inhibitors by blocking the access of the natural substrate to the active site of PqsD reduced the production of HHQ by P. aeruginosa Allegretta et al. Furthermore, the enzyme PqsBC, which catalyzes the condensation of octanoyl-CoA and 2-aminobenzoylacetate rendering HHQ is also a QS inhibitor target.

In this regard, it was observed that the PqsBC competitive inhibitor 2-aminoacetophenone 2-AA affected HHQ production by the recombinant P.

putida KT strain Drees et al. However, strategies focused on PqsBC inhibition could carry unwanted effects. The PqsBC substrate 2-aminobenzoylacetate could transform in 2-AA or 2,4-dihydroxyquinoline DHQ Dulcey et al.

The 2-AA promoted the emergence of persister cells in pathogens as P. aeruginosa, A. baumannii and Burkholderia thailandensis , whereas DHQ has been linked to P.

aeruginosa pathogenicity Que et al. In this regard, it has been demonstrated that the treatment of a P. aeruginosa mvfR mutant constitutively expressed the pqs ABCDE operon with some benzamide-benzimidazole compounds PqsBC inhibitors may provoked the accumulation of 2-AA and DHQ Maura et al.

In addition, in the P. aeruginosa PA14 parental strain, the treatment with some of these PqsBC inhibitors specifically those also contain a low anti-MvfR PqsR activity did affect only partially the production of 2-AA and DHQ and did not inhibit the tolerance to meropenem Maura et al.

In another study performed by Allegretta et al. aeruginosa PA14 and a PA 14 pqsH mutant with PqsBC inhibitors, produced an increase at 2-AA and DHQ levels.

One of these PqsBC inhibitors increased the subpopulation of persister P. aeruginosa PA14 cells to levels similar to a pqsBC mutant strain Allegretta et al.

Interestingly, in this study it was observed that treatment with PqsBC inhibitors increased the 4-hydroxyheptylquinoline-N-oxide HQNO levels. This molecular specie has been also linked to the emergence of antibiotic tolerance in P.

aeruginosa Hazan et al. HQNO appears to boost bacterial autolysis with the subsequent DNA release, which facilitates biofilm formation making the pathogen more tolerant to antibiotics Hazan et al. Moreover, the HQNO produced by P.

aeruginosa also influence the S. aureus susceptibility to antibiotics Orazi and O'Toole, ; Radlinski et al. In another study, it was shown that P. aeruginosa Δ pqsB and Δ pqsC mutants that only produce DHQ, were more virulent in C.

elegans than a quinolone-null mutant Δ pqsAB. An increased colonization capacity of C. elegans was observed for the Δ pqsB mutant in comparison with the Δ pqsAB mutant Gruber et al.

Additional support for the feasibility of using QS signal biosynthesis inhibitors in vivo was demonstrated by the use of ambuic acid as an anti-virulence compound in a murine model of intradermal MRSA challenge.

The treatment with ambuic acid impaired the virulence exerted by S. aureus in the infected animals, as it attenuated skin ulcer formation and the signs of infection-induced morbidity.

The anti-virulence effect of ambuic acid was mediated by inhibition of the agr quorum sensing system Todd et al. Among the quorum quenching strategies one of the most exploited is the inactivation of QS signals LaSarre and Federle, This is a strategy that exists in the natural interactions between microbial populations, and it has been extrapolated as an approach to modulating the virulence of bacterial pathogens.

This virulence modulation through interference with QS signal is centered mainly on the use of QS signal-degrading enzymes LaSarre and Federle, ; Fetzner, The advantage of this strategy is that it targets the QS signal after it is secreted to extracellular medium.

Therefore, there is greater access to the target and challenges associated with penetrating bacterial cells are avoided. Moreover, as an extracellular factor is targeted, the emergence and spread of resistance could be less probable, but potential resistance mechanisms have been envisioned Defoirdt et al.

The most thoroughly characterized quorum quenching enzymes are acyl-homoserine lactone acyl-HSL lactonases, acyl-HSL acylases, and acyl-HSL oxidoreductases, which target the QS signal acyl-homoserine lactones acyl-HSLs Fetzner, The acyl-HSL lactonases and acyl-HSL acylases destroy acyl-HSL molecules via homoserine lactone ring hydrolysis specifically the ester bond or amide bond hydrolysis between the acyl tail and the homoserine lactone ring, respectively.

Otherwise, the acyl-HSL oxidoreductases modify acyl-HSLs molecules chemically via oxidation or reduction of the acyl chain instead of degrading them LaSarre and Federle, ; Fetzner, Other types of quorum quenching enzymes that have been characterized include E.

coli LsrK kinase that targets the AI-2, and dioxygenases Hod from Arthrobacter sp. Rue61a, AqdC1 and AqdC2 from Mycobacterium abscessus subsp abscessus and Rhodococcus erythropolis BG43 that target alkylquinolone-type molecules Pustelny et al.

LsrK catalyzes the phosphorylation of AI-2 molecules, rendering phospho-AI-2, whereas dioxygenases mediate a dioxygenolytic cleavage of PQS, rendering N-octanoylanthranilic acid and carbon monoxide Pustelny et al. The potential for using quorum quenching enzymes in clinical infection treatment is supported by several studies.

Recently, Utari et al. aeruginosa infection and showed the efficacy of intranasally administered PvdQ acylase in hindering P. aeruginosa virulence. In a lethal infection model, PvdQ-treated animals presented a 5-fold lower bacterial load than non-treated animals, as well as a longer survival time.

Moreover, PvdQ-treated mice showed lower lung inflammation, CXCL2 and TNF-α levels than non-treated animals in a sub-lethal infection model.

It is noteworthy that intranasally supplied PvdQ acylase was shown to be safe as it was well tolerated by animals Utari et al. Previously, using a Caenorhabditis elegans infection model, the potential of PvdQ acylase as an anti-virulence agent had been shown Papaioannou et al.

Penicillin V acylases Pa PVA and At PVA from the Gram-negative bacteria Pectobacterium atrosepticum and Agrobacterium tumefaciens also exerted quorum quenching activity on P. The supplementation of these two acylases to P. aeruginosa PAO1 provoked a reduction in 3-oxo-C 12 -HSL levels, elastase activity, pyocyanin and biofilm production.

In addition, the survival rates of G. mellonella infected with P. aeruginosa PAO1 pre-treated with acylases were higher than G. mellonella larvae infected with P. aeruginosa PAO1 without acylases pre-treatment Sunder et al.

Another quorum quenching enzyme that has been tested in vivo is the engineered lactonase Sso Pox-WI. Using an acute lethal model of P. aeruginosa pneumonia in rats, Hraiech et al.

aeruginosa PAO1 significantly reduced the mortality rate and the lung damage. Sso Pox-WI was well tolerated by rats Hraiech et al.

Recently, Sso Pox-WI showed anti-virulence activity against clinical P. aeruginosa isolates. Interestingly, Sso Pox-WI immobilization did not affect the anti-virulence activity against P. aeruginosa PAO1 Guendouze et al.

Moreover, AiiM lactonase attenuated P. aeruginosa PAO1 virulence in an acute pneumonia murine model. Mice infected via intratracheal with an AiiM-expressing P. aeruginosa PAO1 strain showed less lung injury, lower pro-inflammatory cytokines levels, and lower mortality than animals infected with an AiiM-nonexpressing P.

aeruginosa PAO1 strain. In addition, in AiiM-expressing P. aeruginosa PAO1 infected mice there was a reduced systemic dissemination of the infection in comparison with the AiiM-nonexpressing P.

aeruginosa PAO1 infected ones Migiyama et al. Based on a C. elegans infection model it was demonstrated that lactonase MomL from Muricauda olearia increased the survival of P.

aeruginosa PAO1-infected nematodes without showing toxic effects. However, a protective effect was not observed in A. baumannii- infected nematodes Tang et al. Furthermore, recently discovered quorum-quenching enzymes show potential as anti-virulence agents.

Lactonases AaL isolated from Alicyclobacillus acidoterrestris , AiiK from Kurthia huakui LAM T and Aii from Mao-tofu metagenome, inhibited virulence factors production and biofilm formation by A.

baumannii and P. aeruginosa PAO1 without affecting bacterial growth Fan et al. Another newly described quorum-quenching enzyme is AidA, which was identified in A. baumannii clinical isolates López et al. In addition to quorum-quenching enzymes, QS signal inactivation is also reached by the action of anti-QS signal antibodies and synthetic polymers that sequester it Piletska et al.

The use of antibodies with therapeutic aims offers desirable effects, such as high specificity to the target coupled with low off-target cytotoxicity Palliyil et al.

However, developing anti-QS signal antibodies is a challenging task, because these signals are small size molecules and generally not structurally complex, making them poor antigens Palliyil et al.

Despite this, several studies support the potential of antibodies in disturbing quorum-sensing networks. Recently, centered on the agr type I quorum-sensing system of S.

aureus , a virus-like particle VLP -based agr type I vaccine was developed using a P. aeruginosa RNA bacteriophage PP7 coat protein inserted with a S.

aureus sequence-modified autoinducer peptide-1 AIP1S, cysteine was substituted by serine, YST S DFIM. In this vaccinal candidate PP7-AIP1S the AIP1S peptide was exposed on the surface of the VLP, and immunized mice with PP7-AIP1S developed antibodies that specifically recognized the original S. aureus AIP1 in vitro.

In addition, using a murine model of S. aureus SSTI skin and soft tissue infection , it was observed that after a challenge with a virulent S.

aureus USA isolate LAC agr -type I , in PP7-AIP1S immunized mice reduced agr -type I-mediated pathogenesis was developed, compared to the non-immunized animals.

Reduced alpha-hemolysin levels, as well as RNAIII transcription at the infection site in the immunized animals, together with the in vitro antibodies binding from immunized animals to AIP1 suggested the occurrence of immune suppression of agr -signaling during the infection Daly et al.

Using a peptide library displayed on VLP, O'Rourke et al. This monoclonal antibody specifically bound and neutralized the autoinducer peptide-4 AIP4 from S. aureus and protected animals from S. aureus pathogenicity, as was shown previously by Park et al. From the eight APHbonding VLP-peptides, two of them, when administered alone, apparently induced a protective response reduced abscess and dermonecrosis against S.

aureus agr -type IV isolate AH infection in immunized mice. Additionally, the immunization of mice with a combination of these two VLP-peptides protected those from S. aureus AH infection via inhibition of agr- signaling O'Rourke et al. Furthermore, it was observed that sheep-mouse chimeric monoclonal antibodies with affinity in the nanomolar range against HSL molecules protected C.

elegans nematodes and mice infected with P. aeruginosa PA In infected mice, this protection appears to be associated with the antibody-mediated scavenging of HSL molecules and not by effects on the bacterial load Palliyil et al.

Moreover, immunized mice with 3-oxo- dodecanoyl homoserine lactone conjugated to BSA 3-oxo-cHSL-BSA developed specific antibodies against the HSL and intermediate protection was observed after intranasal infection with P.

aeruginosa PAO1. Interestingly, the lung bacterial burden was not affected in the immunized mice, and the levels of TNF-α lung and 3-oxo-cHSL lung and serum were lower than in non-immunized animals Miyairi et al. In addition to interference with QS signaling, monoclonal antibodies against QS signal molecules also protect from cytotoxic effects exerted by these molecules on host cells.

Kaufmann et al. Previously, it was demonstrated that serum from immunized animals with 3-oxo-CHSL-BSA inhibited the autoinducer-dependent apoptosis of the macrophage cell line PD1 Miyairi et al.

Synthetic polymers constitute another alternative for interference with QS signal. These polymers bind and sequester the QS signal without affecting bacterial growth; therefore, they should not exert selective pressure.

A pioneering work by Piletska et al. The sequestering of 3-oxo-C6-HSL by the polymers impaired the bioluminescence production as well as biofilm formation Piletska et al.

In a subsequent work by this group, it was showed that an itaconic acid IA -based-molecular imprinted polymer MIP impaired P. aeruginosa biofilm formation by sequestering the 3-oxo-CHSL QS signal Piletska et al. Moreover, linear polymers IA-based polymers and methacrylic acid-based polymers reduced V.

fischeri bioluminescence and Aeromonas hydrophila biofilm production through lactones sequestering. The IA-based polymers were more effective than methacrylic acid-based polymers regarding the quorum-quenching activity.

Importantly, the polymers did not show cytotoxic effects on mammalian cells and did not affect bacterial growth Cavaleiro et al.

Recently, it was observed that 2-hydroxyethyl methacrylate HEMA -based MIPs suppressed the biofilm formation by P. aeruginosa ; however, IA-based MIPs were not effective in the biofilm attenuation Ma et al. Interference with signal detection is another of the most exploited strategies for disrupting QS systems.

Some of these QS signal detection inhibitors are signal structural analogs that compete with the signal molecule by binding at the ligand-binding site in the receptor Stevens et al. Moreover, other inhibitors could act in a non-competitive fashion e. The inhibitors binding to the receptors directly affect the signaling cascade by different pathways, including block signal binding, structural destabilization of the receptor, impaired receptor dimerization, impaired DNA binding, or impaired interaction with RNA polymerase Stevens et al.

Moreover, it has been shown that agonists of the QS signal can also exert inhibitory activity on QS systems.

Some QS circuits are arranged in hierarchically cross-regulated networks, e. aeruginosa the las -QS system positively regulates rhl - and pqs -QS systems, in addition the activated pqs -QS system also positively regulates the rhl -QS system, whereas this exerts negative regulation on the pqs -QS system Lee and Zhang, Therefore, by modulating the activity of one QS system, it is possible to influence the activity of the other QS systems.

In this respect, Welsh et al. Disruption of cross-regulation of rhl - pqs systems was proposed as a novel mechanism of QS inhibition Welsh et al. The use of small molecules to disturb QS signal detection has to face several challenges.

In this respect, structural stability of the inhibitors is a very important issue; some structural analogs of HSLs and AIPs are prone to hydrolysis, depending on the characteristics of the media Glansdorp et al.

In addition, inhibitors could be potentially degraded by enzymes as well as targeted by efflux pumps Maeda et al. Moreover, the inhibitory effect observed could be strain-dependent, and it is therefore important to include several strains in the studies García-Contreras et al.

Despite the challenges, the feasibility of QS signal detection inhibition as a quorum-quenching strategy is supported by several in vivo studies.

aeruginosa , and RhlR inhibition is its main mechanism of action in vivo. This compound potently inhibited P. aeruginosa PA14 pyocyanin and biofilm production without affecting bacterial growth. In addition, the treatment of P. aeruginosa PA14 with mBTL down-regulated the expression of several LasR- and RhlR-controlled virulence factor genes.

The treatment of wild-type and P. aeruginosa PA14 lasR mutant strains with mBTL reduced the pathogenesis exerted by these strains in C. elegans and human lung carcinoma cell line A O'Loughlin et al.

Another inhibitor of P. aeruginosa HSL-based QS systems that has been tested in vivo is the fungal metabolite terrein. aeruginosa PAO1 with terrein provoked a reduction in a dose-dependent manner in the production of virulence factors elastase, pyocyanin, and rhamnolipid as well as in biofilm formation without affecting bacterial growth.

In addition, terrein showed to be more stable than the QS inhibitor furanone C and enhanced the anti-biofilm activity of ciprofloxacin when used in combination. Importantly, terrein mediated protection of C. elegans and mice against P. aeruginosa PAO1infection in a fast killing infection assay and murine airway infection model, respectively.

Interestingly, it was observed that the QS system and c-di-GMP signaling pathway could be interconnected, and that terrein could act as a dual inhibitor of these systems Kim et al.

Moreover, HSL analogs that act as covalent inhibitors of LasR receptor were seen to be promising in vivo tests. Specifically, the isothiocyanate- and fluoroisothiocyanate-based covalent inhibitors ITC and ITC-F, respectively attenuated the virulence of P.

aeruginosa PAO1-UW and consequently increased the survival of C. elegans worms during an infection assay with this pathogen. The ITC-F treated group showed a significant survival rate in comparison with the control group.

Moreover, using an ex-vivo human skin burn wound model it was observed that ITC-F and ITC treatment impaired the establishment of infection by P. aeruginosa PA14 Amara et al. In addition to HSL-based QS systems in P. aeruginosa , the PQS-based QS system is also involved in the regulation of virulence factor production.

In this regard, maybe inhibitors that could affect these two QS system types would be desirable. Among them, 3-Phenyllactic acid PLA is an organic compound produced by Lactobacillus spp that acts as a QS sensing inhibitor that potentially could bind to RhlR and PqsR receptors with high affinity Chatterjee et al.

Recently, Chatterjee et al. aeruginosa PAO1 on a catheter tube, using a Medaka fish intraperitoneal catheter-associated infection models Chatterjee et al. Furthermore, agr -QS system inhibition has been shown to be an achievable strategy for controlling the virulence of pathogens like S.

In this regard, atopic dermatitis is a chronic inflammatory skin disease where S. aureus triggers an immunopathology response through mast cell degranulation.

This mast cell degranulation could be induced by the bacterial δ-toxin, which is encoded by the hld gene that is under control of the agr- QS system Baldry et al.

Recently, the effectiveness of the agr -QS inhibitor solonamide B in suppressing the S. aureus δ-toxin-induced-inflammatory response was tested using a modified epicutaneous colonization mouse model.

Animals infected with S. aureus and treated with solonamide B showed a reduced skin inflammatory cell infiltrate, less skin damage, reduced RNAIII expression and production of pro-inflammatory cytokines in comparison to non-treated animals, suggesting that agr -QS inhibitors could effectively attenuate S.

aureus pathogenesis in vivo Baldry et al. In addition to the use of quorum quenching enzymes and quorum sensing inhibitors, some innovative therapeutic strategies to interfere with quorum sensing networks are being developed. One of the challenges in disrupting quorum sensing networks is the fact that a pathogen may possess several QS systems of the same class, for example P.

aeruginosa contains the AHL-based systems LasRI and RhlRI Lee and Zhang, Therefore, acquiring complete inhibition of the QS systems using quorum-quenching enzymes or quorum-quenching inhibitors in a monotherapy-based scheme could be difficult Fong et al.

Based on this challenge, Fong et al. It was observed that combinatory therapy inhibited the expression of lasB-gfp, pqsA-gfp , and rhlA-gfp in P. aeruginosa PAO1 bioreporter strains more potently than single treatments. The rhlA gene is involved in the biosynthesis of rhamnolipid and is under RhlR-transcriptional regulation.

In accordance with this, the inhibitory effect on rhamnolipid biosynthesis was verified in a P. The level of synthetized rhamnolipid in the combinatory therapy-treated bacteria was nearly to the rhamnolipid level in a Δ lasI Δ rhlI mutant strain Fong et al.

All this evidence suggests that using combinatory therapy with different types of quorum-quenching agents it is possible to disturb diverse quorum-sensing systems existing in pathogens.

In the combinatory therapy described above, a multi-target effect is achieved by joining two therapeutic agents that target different components in the QS networks.

However, it is possible to get the same multi-target effect using a single compound Thomann et al. Recently a drug with dual inhibitory activity toward the PqsR and PqsD components of the P. aeruginosa pqs QS system was developed. This dual inhibitor [2- methylsulfonyl 1H-tetrazolyl pyrimidine] was developed from a common molecular scaffold existing in single PqsR- antagonist and PqsD-inhibitor.

In vitro analysis showed that the dual inhibitor disturbed the production of the virulence factors pyocyanin and pyoverdine as well as the biofilm production by P. In addition, the dual inhibitory compound increased the survival rate of G.

aeruginosa PA14 Thomann et al. Moreover, Maura et al. These dual inhibitory compounds targeted the proteins PqsR MvfR and PqsBC and could be grouped depending on their inhibition patterns in: PqsR-PqsBC dual inhibitors with high anti-PqsR and high anti-PqsBC activity or PqsR-PqsBC dual inhibitors with low anti-PqsR activity and high anti-PqsBC activity.

The treatment with some of these dual inhibitors increased the survival rate of human lung epithelial cells and RAW aeruginosa PA14 Maura et al. Among the dual inhibitors, those exert a high anti-PqsR activity constitute an attractive therapeutic option because interfere with the production of 2-AA and consequently limit the emergence of antibiotic-tolerant bacteria as was previously discussed.

coli e. This microbial-control device consisted of engineered mammalian cells with a formyl peptide sensor module coupled to AI-2 production and release module. Essentially, the engineered mammalian cells detect formyl peptides released by pathogens peptides produced by a broad range of bacterial species and trigger the production and release of AI It was showed that biofilm formation by Candida albicans was reduced when this pathogen was co-cultured with microbial-control-engineered cells.

This system appears to be a promising anti-virulence strategy, as ubiquitous pathogen signals are detected with high sensitivity nM range , and robust production of the autoinducer takes place without being toxic for the host influencing bacterial communication without exerting selective pressure.

In addition, the fact that autoinducer production is coupled to signal detection allows a synchronized response in accordance with the infection dynamic Sedlmayer et al. Moreover, it possible to engineer bacteria that will sense the presence of pathogenic bacteria via the quorum sensing system and, once detected, will release anti-pathogens agents.

Hwang et al. coli Nissle strain for sense 3-oxo-C12 HSL from P. aeruginosa and respond by autolysing itself via lysin E7 with the consequent release of the bacteriocin pyocin S5 and the anti-biofilm enzyme DspB, which exerted an anti- P. aeruginosa activity. The feasibility of this approach was demonstrated in vivo using C.

elegans and murine infection models, where the engineered strain showed prophylactic and therapeutic effects Hwang et al. Although the strategy of interference with autoinducer biosynthesis has been based on the discovery and design of small molecules that inhibit the enzymatic activity, it has been envisioned that engineered bacterial strains could be an alternative.

Recently, it was showed that it is possible to disrupt biofilm production in clinical isolates through the manipulation of the expression levels of the enzyme LuxS. Specifically, using the Clustered Regularly Interspaced Short Palindromic Repeats-Cas 9 interference CRISPRi system, the expression of LuxS enzyme was suppressed in clinical E.

coli isolates. It was suggested that CRISPRi edited cells could be an alternative strategy for controlling biofilm production in nosocomial settings through CRISPRi system delivery via nucleic acid conjugation Zuberi et al. However, delivery of CRISPRi system in nosocomial setting via nucleic acid conjugation could be a very challenging task.

Given the fact that nucleic acid conjugation could occur between different bacterial species Musovic et al. In this regard, maybe the utilization of narrow host range plasmids as vectors for CRISPRi delivery could limit such potential off-target effect.

In addition, the nucleic acid conjugation effectivity in established biofilms could be compromised Merkey et al. This could limit the use of CRISPRi edited cells for the treatment of formed biofilms. In this sense, maybe the utilization of engineered phages as vehicles for CRISPRi system delivery could be an attractive alternative.

Phages have shown be a CRISPR delivery system with specificity to pathogenic bacteria as well as with capacity to removing established biofilms Lu and Collins, ; Bikard et al. Bacteria can live in a community called biofilm, a structure that can be formed by extracellular polymeric substances, such as DNA, protein, and polysaccharides Flemming et al.

After forming biofilms, bacteria can disperse and colonize other environments Fleming and Rumbaugh, This lifestyle can protect bacteria against potential environmental stress, such as antibiotics and host defense components Hall and Mah, ; Tseng et al.

In the clinical situation, biofilm formed by pathogenic bacteria can establish themselves on human surfaces or medical devices, including implants, catheter, endotracheal tubes and others Rieger et al. Biofilm formation on these surfaces can serve as a source of infection.

The successful establishment of pathogenic biofilm on human surfaces can cause chronic infections and limit the success of antibiotic therapy Rybtke et al. In general, combating biofilms may require high antibiotic doses and a combination of strategies Ribeiro et al.

Unfortunately, many of the marketed antibiotics fail to affect biofilm, especially if they are formed by resistant bacteria. In both situations, anti-biofilm agents can be represented by a variety of organic and inorganic chemical compounds Rajput et al. Anti-virulence compounds against biofilms could be used to limit bacterial adhesion on surfaces Liu et al.

Some examples of anti-virulence compounds cited here work against non-pathogenic bacteria to humans and animals. However, the approaches using these bacteria may serve as proof of principle to study anti-virulence compounds against biofilms in a general way. In the prevention scenario, one possibility consists of interfering with structures associated with the successful establishment of biofilms such as flagella that favor the bacterial motility and interaction with surfaces and fimbriae with structures that facilitate bacterial adhesion.

Higrocin C a compound isolated from marine-derived Streptomyces sp. SCSGAA for example, suppressed swimming motility of Bacillus amyloliquefaciens SCSGAB, which could explain the biofilm inhibition Wang et al. Transcriptome studies showed downregulation more than twofold of genes associated with bacterial chemotaxis and flagellar motor Wang et al.

Coumarin, for example, presents the ability to prevent bacteria biofilm without affecting bacterial growth Lee et al. This compound repressed curli genes and motility genes in E. coli OH7 and reduced fimbriae production, swarming motility, and biofilm formation Lee et al.

Another way to prevent biofilm formation consists of affecting the extracellular matrix production. subtilis biofilm formation by reducing extracellular matrix production. This was associated with the repression of SinR protein negative regulated genes involved in extracellular matrix production Feng et al.

Other studies have shown that compounds that prevent biofilm formation can potentially affect bacterial cell communication by degrading quorum-sensing molecules Ivanova et al. In the context of combating existing biofilms, compounds can be used to destroy components of extracellular matrix, such DNA, proteins and carbohydrates Puga et al.

In this context, enzymes have been used as potential agents to disrupt mono and polymicrobial biofilm Puga et al. DNAse I, for example, presents the ability to degrade extracellular DNA of Campylobacter jejuni , promoting biofilm removal without affecting bacterial viability Brown et al.

The understanding of mechanisms involved in the formation of bacterial biofilm, as well as the understanding of their cells and biofilm structures, could indicate possible targets to develop compounds that affect biofilm without killing bacteria.

In addition to potential anti-biofilm therapy, agents that can prevent or disperse biofilm could potentially combine with anti-virulence compounds.

For example, anti-virulence agents could be used to neutralize endotoxins from bacterial cells that disperse from biofilms and thus prevent or minimize the harmful effects of the host inflammatory response against bacterial infection. It is known that pathogenic bacteria may produce diverse virulence determinants in order to successfully survive host system responses, as well as colonizing a host Kong et al.

Among them, toxins comprise proteins expressed by bacteria during post-exponential and early stationary phases that have been divided into different classes, including hemolysin Powers et al.

These protein-based toxins are intrinsically related to physical damage, biochemical degradation and signaling interruption in the host cells, resulting in immune system evasion and characterizing pathogen-to-host interactions Wei et al.

Bacterial toxin neutralization, for instance, has been shown to compromise bacterial proliferation and survival in the host Ortines et al. More importantly, unlike antibiotic-based treatments, anti-toxin or anti-virulence therapies do not affect bacterial viability directly and, as a consequence, could impose reduced selective pressure, probably decreasing the frequency of resistance events Rasko and Sperandio, In addition, anti-virulence compounds are also known to preserve the host's endogenous microbiome as they target virulent factors secreted exclusively by pathogenic bacteria Clatworthy et al.

In this context, here we described compounds, including antibodies, nanoparticles, small molecules, and bioactive peptides Figure 1 and Table 1 , which have been studied recently as promising candidates for anti-virulence therapies that aim to treat and prevent bacterial infections.

The α-toxin AT , also known as α-hemolysin, is a key virulence factor expressed by S. This toxin is capable of lysing red blood cells, and also targets monocytes, macrophages and neutrophils Bubeck Wardenburg et al.

Moreover, in the clinic, AT levels in patients are often correlated with disease severity Jenkins et al. Studies have shown that rabbits with acute bacterial skin and skin structure infections ABSSSI caused by AT-expressing methicillin-resistant S.

aureus MRSA develop severe infections similar to those observed in humans, including the presence of large dermonecrotic lesions.

In contrast, rabbits infected with a mutant deficient AT strain developed only small dermonecrotic lesions Le et al. One major anti-virulence strategy to neutralize AT consists of using antibodies.

Similarly, Ortines et al. Moreover, those authors also showed the differential host immune response effects, revealing different patterns of macrophage, monocyte and neutrophil infiltrates, as well as neutrophil extracellular traps NETs in non-diabetic and diabetic mice Ortines et al.

In addition to skin infections, S. aureus strains are often associated with respiratory mono-infections and co-infections with Gram-negative strains, including P.

aeruginosa and Klebsiella pneumoniae. In a study by Cohen et al. aureus AT, in a mixed pathogen-lung infection model, could potentiate Gram-negative bacterial dissemination and lethality.

This situation, however, could be circumvented by the passive immunization of mice with an anti-AT mAb, leading to S. aureus and co-pathogens Gram-negative bacteria clearance in the lungs Cohen et al. Additionally to mAb, the intravenous immunoglobulin IVIG , which consists of a polyclonal human antibody pool, has been investigated regarding its protective effects against necrotizing pneumonia caused by different epidemic community-associated and hospital-associated MRSA strains Diep et al.

As reported by Diep et al. In the clinic, patients affected by bacteremia, including S. aureus , may present occlusion of small blood vessels by the formation of large platelet aggregates van der Poll and Opal, In a recent study, it was reported that AT induces rapid platelet aggregation and liver injury, causing multi-organ dysfunction during S.

aureus sepsis Surewaard et al. More recently, Wang et al. In that work, the authors purified EVs from a genetically engineered S. aureus capable of overexpressing detoxified cytolysins HlaH35L and LuKE , which were non-toxic, immunogenic and protected mice from lethal sepsis caused by S.

aureus Wang et al. Also in the field of S. aureus toxin neutralization, the monoclonal antibody, ASN Arsanis Inc. aureus toxins Rouha et al.

Despite the advances in the usage ASN in the clinic, the company Arsanis Inc. has discontinued a phase II clinical trial for ASN as it failed to prove its effectiveness in high-risk, mechanically ventilated patients with S.

aureus pneumonia. Antibodies have also been applied as anti-virulent therapies involving Clostridium difficile , which represents a primary cause of nosocomial antibiotic-related diarrhea. This bacterium produces two main virulence factors, toxin A TcdA and toxin B TcdB , responsible for gastrointestinal epithelial damage and colonic inflammation.

difficile infections. With that in mind, Andersen et al. difficile strain. Initially, in vitro studies were carried out to confirm the ability of the expressed fragments in neutralizing the cytotoxic effect of TcdB. Moreover, in vivo assays revealed that Lactobacillus strains expressing two TcdB-neutralizing antibodies led to improved survival rates in the treated group.

Furthermore, the protection with TcdB-neutralizing antibodies also preserved the gastrointestinal tract of the animals as no damages or limited inflammation were observed Andersen et al.

In addition to antibody-based therapies, studies have also explored the potential of small molecules as inhibitors of C. difficile TcdB. Tam et al. As a result, the authors reported a series of small molecules with diverse mechanisms of action on TcdB, including direct binding, sequestration of TcdB, non-competitive inhibition of the glucosyl-transferase activity of TcdB, as well as endosomal maturation inhibition Tam et al.

However, in vivo studies are still underway to confirm the effectiveness of these small molecules in C. Apart from the application of anti-toxin antibodies and small molecules in anti-virulence therapies, studies have also highlighted the importance of engineered nanoparticle mimicking cell membranes e.

Artificial liposomes are constituted exclusively of natural lipids and therefore are not active against bacteria, thus allowing their usage in combination with antibiotics for bacterial infection treatment. Henry et al. The authors also observed that, during in vivo experiments, the administration of artificial liposomes resulted in mice recovering from septicemia caused by S.

aureus and Streptococcus pneumoniae , as well as mice being protected against pneumonia Henry et al. Moreover, combining the artificial liposomes with conventional antibiotics, including vancomycin and penicillin, improved survival rates were observed when compared to mono-therapies Henry et al.

Bacteria secrete a wide variety of toxins during host colonization and infection, which represents a bottleneck when it comes to vaccine development aiming at anti-virulence therapies. Indeed, vaccine strategies based on multiple targets bacterial toxins have already been reported; however, the identification and further confirmation of virulence factors secreted by bacteria is considered a costly and time-consuming method Fujita and Taguchi, As an alternative, studies have proposed the use of multiantigenic nanotoxoids based on naturally occurring bacterial proteins to develop vaccines against pathogenic bacteria.

Wei et al. As for the other anti-virulence therapies here described, the nanoparticle-based neutralization and delivery not only usefully prevent severe bacterial infections but also decrease the risk of antibiotic resistance events Wei et al. Besides the secretion of protein-based toxins, the bacterial LPS in the host's blood stream is known to cause severe immune system stimulation, resulting in septic shock and sepsis Rietschel et al.

Among the strategies to neutralize LPS, the application of antimicrobial peptides AMPs has shown promising results. Moreover, the mechanisms of action and structural arrangements of some AMPs in contact with LPS have already been investigated, including polymyxins Pristovsek and Kidric, , temporins Bhunia et al.

This class of antimicrobials is well known for its multifunctionality and structural diversity. Studies have shown that AMPs with extended activities, including immunomodulatory, are capable of binding to LPS and, consequently, decreasing the production of nitric oxide and tumor necrosis factor-α TNF-α , which are commonly related to tissue damage Pulido et al.

Chih et al. Interestingly, the authors observed that LPS-neutralizing activities were directly related to the addition of β-naphthylalanine end-tags in both peptides, which was also reflected in the dose-dependent inhibition of nitrite oxide production and TNF-α release in vitro and in vivo Chih et al.

In addition, other AMPs, including members from the Pep The antimicrobial resistance threat has driven the global scientific community to search for effective solutions. Given the fact that antimicrobial resistance is a multifactorial phenomenon, the solution for this problem involves a range of approaches focused on controlling the factors that facilitate the emergence and spread of resistance.

One of these approaches consists of developing new therapeutic agents that operate under different principles to the currently available antibiotics. In this respect, anti-virulence therapy has been envisioned as a promising alternative with the aim of controlling pathogen virulence in a pathogen-specific fashion, without exerting strong selective pressure on the pathogens.

However, as an emerging therapeutic strategy, anti-virulence therapy has to face several challenges. The selection of the targeted virulence factor s is of critical importance for the effectiveness of the strategy in terms of evolutionary robustness.

In line with this, a suitable target should be a virulence factor whose disruption does not imply or imply minimal fitness consequences for the pathogen Vale et al. Moreover, a virulence factor that is conserved between different pathogens could be ideal, because in principle it would be possible to treat polymicrobial infections with a single anti-virulence drug Maura et al.

It is necessary to understand the detailed dynamics of action of the targeted virulence factor as well as the dynamics of production Dickey et al. For example, during P. aeruginosa infection of cystic fibrosis patients take place an acute to chronic infection transition.

This shift involves down-regulation of virulence factors as the flagellum, T3SS secretion system, proteases, and others; while virulence factors as exopolysaccharides are up-regulated Hogardt and Heesemann, ; Sousa and Pereira, Therefore, the anti-virulence agent that target some of these virulence factors should be supplemented in accordance with this dynamic of expression.

In addition to knowing the targeted virulence factor production dynamics, it is important to know if this virulence factor undergoes chemical modifications that modulate its activity.

Furthermore, as anti-virulence therapy works in a pathogen-specific fashion, it is important to have diagnostic methods like matrix-assisted laser desorption ionization-time of flight mass spectrometry MALDI-TOF , microarray-based nucleic acid test, magnetic resonance-based diagnostic, fluorescence in situ hybridization FISH test, next generation sequencing NGS and multiplex PCR-based diagnostic test, which permit rapid and precise identification of the infection-causing pathogen Dickey et al.

It is also mandatory to define which parameters will be taken into account for measuring the effectivity of the anti-virulence therapy and for which type of infection the therapy is most suitable Maura et al.

For example, in certain types of S. aureus infections e. Moreover, recently it has been reported that defective agr -QS system could mediate the tolerance to certain antibiotics gentamicin and ciprofloxacin; Kumar et al. In addition, it has been suggested that phenol-soluble modulin toxins PSMs are involved in the control of S.

aureus persister cells population Bojer et al. Because the PSMs production is under the control of the agr -QS system, it is probably that a defective agr -QS system down-regulate the expression of PSMs which could favor the emergence of persister cells to certain antibiotics.

Therefore, in the above-pointed situations maybe anti-virulence therapies based on agr -QS system inhibition could be not a feasible strategy. Although anti-virulence therapy is an emerging field, several potential anti-virulence drugs have already been identified, and existing chemical libraries for antibiotic discovery could be a valuable source for rapid identification of novel anti-virulence drugs Maura et al.

At this point, it is necessary to direct these potential anti-virulence candidates toward pre-clinical and clinical trials. OF, MC, and SR wrote the manuscript. MC performed the figures. OLF designed and revised the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abbas, H. Repurposing metformin as a quorum sensing inhibitor in Pseudomonas aeruginosa.

Health Sci. doi: PubMed Abstract CrossRef Full Text Google Scholar. Glyceryl trinitrate is a novel inhibitor of quorum sensing in Pseudomonas aeruginosa. Alberts, A. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

Allegretta, G. In-depth profiling of MvfR-regulated small molecules in Pseudomonas aeruginosa after quorum sensing inhibitor treatment. Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.

Alves, D. A novel bacteriophage cocktail reduces and disperses Pseudomonas aeruginosa biofilms under static and flow conditions. Amara, N. Fine-tuning covalent inhibition of bacterial quorum sensing.

Chembiochem 17, — Andersen, K. Neutralization of clostridium difficile toxin B mediated by engineered lactobacilli that produce single-domain antibodies. Arya, R. Exploration of modulated genetic circuits governing virulence determinants in Staphylococcus aureus. Indian J. Bach, J. Flotillins functionally organize the bacterial membrane.

Badarau, A. Context matters: The importance of dimerization-induced conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of neutralizing antibodies.

MAbs 8, — Baldry, M. The agr inhibitors solonamide B and analogues alter immune responses to Staphylococccus aureus but do not exhibit adverse effects on immune cell functions. PLoS ONE e CrossRef Full Text Google Scholar.

Application of an agr-specific anti-virulence compound as therapy for Staphylococcus aureus -induced inflammatory skin disease. Bergonzi, C. Structural and biochemical characterization of AaL, a quorum quenching lactonase with unusual kinetic properties.

Bhunia, A. Structural and thermodynamic analyses of the interaction between melittin and lipopolysaccharide. Acta , — NMR structures and interactions of temporin-1Tl and temporin-1Tb with lipopolysaccharide micelles: mechanistic insights into outer membrane permeabilization and synergistic activity.

Bikard, D. Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Birmes, F. Mycobacterium abscessus subsp.

abscessus is capable of degrading Pseudomonas aeruginosa quinolone signals. Bojer, M. Quorum sensing-regulated phenol-soluble modulins limit persister cell populations in Staphylococcus aureus.

Bramkamp, M. Exploring the existence of lipid rafts in bacteria. Brown, H. Campylobacter jejuni biofilms contain extracellular DNA and are sensitive to DNase I treatment.

Bubeck Wardenburg, J. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Bukowski, M. Exfoliative toxins of Staphylococcus aureus. Toxins 2, — Calfee, M. Interference with Pseudomonas quinolone signal synthesis inhibits virulence factor expression by Pseudomonas aeruginosa.

Capilato, J. Development of a novel series of non-natural triaryl agonists and antagonists of the Pseudomonas aeruginosa LasR quorum sensing receptor.

Cattò, C. Unravelling the structural and molecular basis responsible for the anti-biofilm activity of zosteric acid. Cavaleiro, E. Novel linear polymers able to inhibit bacterial quorum sensing.

Chang, E. Catechin-mediated restructuring of a bacterial toxin inhibits activity. Acta General Subjects , — Chatterjee, M. Mechanistic understanding of Phenyllactic acid mediated inhibition of quorum sensing and biofilm development in Pseudomonas aeruginosa. Chih, Y. Ultrashort antimicrobial peptides with antiendotoxin properties.

Agents Chemother. Citorik, R. Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases. Clatworthy, A. Targeting virulence: a new paradigm for antimicrobial therapy. Cohen, T. Staphylococcus aureus alpha toxin potentiates opportunistic bacterial lung infections.

Crémet, L. Nosocomial outbreak of carbapenem-resistant Enterobacter cloacae highlighting the interspecies transferability of the bla OXA gene in the gut flora.

Da, F. Antisense locked nucleic acids targeting agrA inhibit quorum sensing and pathogenesis of community-associated methicillin-resistant Staphylococcus aureus. Daly, S. ω-Hydroxyemodin limits Staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation.

VLP-based vaccine induces immune control of Staphylococcus aureus virulence regulation. Defoirdt, T. Quorum-sensing systems as targets for antivirulence therapy.

Trends Microbiol. Can bacteria evolve resistance to quorum sensing disruption? PLoS Pathog. Dickey, S. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Drug Discovery Diep, B.

IVIG-mediated protection against necrotizing pneumonia caused by MRSA. Dong, W. Characterization of AiiK, an AHL lactonase, from Kurthia huakui LAM T and its application in quorum quenching on Pseudomonas aeruginosa PAO1. Drees, S. PqsBC, a condensing enzyme in the biosynthesis of the Pseudomonas aeruginosa quinolone signal crystal structure, inhibition, and reaction mechanism.

Duan, J. Subinhibitory concentrations of resveratrol reduce alpha-hemolysin production in Staphylococcus aureus isolates by downregulating saeRS. Dulcey, C. The end of an old hypothesis: the Pseudomonas signaling molecules 4-hydroxyalkylquinolines derive from fatty acids, not 3-ketofatty acids.

Edwards, G. Eibergen, N. Potent and selective modulation of the RhlR quorum sensing receptor by using non-native ligands: an emerging target for virulence control in Pseudomonas aeruginosa.

Chembiochem 16, — Fan, X. Aii, a novel cold-adapted N-acylhomoserine lactonase discovered in a metagenome, can strongly attenuate Pseudomonas aeruginosa virulence factors and biofilm formation.

Fang, R. Engineered nanoparticles mimicking cell membranes for toxin neutralization. Drug Deliv. Feng, L. Specific inhibitions of annonaceous acetogenins on class II 3-hydroxymethylglutaryl coenzyme A reductase from Streptococcus pneumoniae.

Feng, X. Structural and functional analysis of Bacillus subtilis YisP reveals a role of its product in biofilm production. Fetzner, S. Quorum quenching enzymes. Fleming, D. Approaches to dispersing medical biofilms. Microorganisms Flemming, H. Biofilms: an emergent form of bacterial life.

Fong, J. Combination therapy strategy of quorum quenching enzyme and quorum sensing inhibitor in suppressing multiple quorum sensing pathways of P. Fong, S. Activity of bacteriophages in removing biofilms of Pseudomonas aeruginosa isolates from chronic rhinosinusitis patients. Fujita, Y. Current status of multiple antigen-presenting peptide vaccine systems: application of organic and inorganic nanoparticles.

Garcia, S. Targeting of Streptococcus mutans biofilms by a novel small molecule prevents dental caries and preserves the oral microbiome. García-Contreras, R.

Is quorum sensing interference a viable alternative to treat Pseudomonas aeruginosa infections? Harmful germs are called pathogens. Antimicrobials is a term used to describe drugs that treat many types of infections by killing or slowing the growth of pathogens causing the infection.

The content on this webpage does not include resistance to antivirals or antiparasitics. Bacteria cause infections such as strep throat, foodborne illnesses, and other serious infections. Antibiotics treat bacterial infections. Antifungals treat fungal infections.

On This Page. How Antibiotic and Antifungal Use Affects Resistance Antibiotics and antifungals save lives, but their use can contribute to the development of resistant germs.

Resistance Mechanisms Defense Strategies Resistance Mechanisms Defense Strategies Description Restrict access of the antibiotic Germs restrict access by changing the entryways or limiting the number of entryways.

Get rid of the antibiotic or antifungal Germs get rid of antibiotics using pumps in their cell walls to remove antibiotic drugs that enter the cell.

Change or destroy the antibiotic Germs change or destroy the antibiotics with enzymes, proteins that break down the drug. Change the targets for the antibiotic or antifungal Many antibiotic drugs are designed to single out and destroy specific parts or targets of a bacterium. Fact Sheets.

How Resistance Spreads. Bacteria and Fungi Fight Back. How Resistance Moves Directly Germ to Germ. Select Germs Showing Resistance Over Time. Top of Page. Last Reviewed: October 5, Source: Centers for Disease Control and Prevention , National Center for Emerging and Zoonotic Infectious Diseases NCEZID , Division of Healthcare Quality Promotion DHQP.

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The Centers for Disease Control and Prevention CDC cannot attest to the accuracy of a non-federal website. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.

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Cancel Continue. Germs restrict access by changing the entryways or limiting the number of entryways.

Sfrategies resistance happens when germs like bacteria and fungi Anti-infection strategies Anti-infectino ability to defeat the drugs Foods to enhance recovery to kill them. That means the germs are not killed and continue to grow. Antimicrobial resistance has been found in every U. state and country. Addressing this threat requires continued aggressive action to:.

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