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The biology and future prospects of antivirulence therapies

An Erratum to this article was published on 01 November 2009

Key Points

  • New therapeutic strategies are urgently needed to improve our chances of success in combating infectious diseases. Bacteria, such as Staphylococcus aureus and Enterococcus faecalis, have emerged in the clinic that are resistant to multiple antibiotics and drugs of last resort.

  • An attractive approach in the discovery of new therapeutics is to target bacterial virulence — that is, to impair processes that are required for a bacterium to establish an infection and cause disease without placing direct life-or-death pressure on the organism. Targeting virulence in this way would help to preserve the many symbioses between the microorganism and host that contribute to human health, but that are radically disrupted by traditional antibacterial therapy.

  • The molecular-level battles between the pathogen and host provide numerous opportunities to impair bacterial progression through an infection cascade (for example, adherence to host cells) and to ameliorate the accompanying consequences to the host (for example, toxin production).

  • Some of the most pursued avenues of antivirulence drug-discovery efforts include those that target bacterial adhesion and toxin production and function. Strategies that aim to impair adhesion and toxin action can act early to prevent the assembly of adhesive machinery or toxin expression or secretion. Alternatively, they can act later to block adhesion using receptor mimics or neutralize toxins, for example, by using antibodies.

  • Additional targets include quorum-sensing systems and two-component response systems, the complexities of which we appreciate and are beginning to dissect in more detail. These are crucial to the genetic and molecular control of the production of virulence factors that are important to many processes, such as adhesion, motility and biofilm formation.

  • In the future, it is imperative that we determine the genetic and molecular bases of bacterial virulence for all organisms and the dynamic exchange during host–pathogen interactions from both the pathogen and host perspectives. New insights are needed to reveal vital genetic or molecular bottlenecks, and to target the 'Achilles' heel' of a pathogen during infection. Ultimately, we may need to combine the strengths of synergistic therapies.

Abstract

The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.

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Figure 1: Multi-step pathogenic cascade of uropathogenic Escherichia coli (UPEC).
Figure 2: Targeting microbial adhesion.
Figure 3: Targeting toxin-powered pathogens.
Figure 4: Pairing quorum sensing and two-component signalling in the staphylococcal agr system.

References

  1. Alekshun, M. N. & Levy, S. B. Molecular mechanisms of antibacterial multidrug resistance. Cell 128, 1037–1050 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Livermore, D. M. Minimising antibiotic resistance. Lancet Infect. Dis. 5, 450–459 (2005).

    Article  PubMed  Google Scholar 

  3. Palumbi, S. R. Humans as the world's greatest evolutionary force. Science 293, 1786–1790 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Vicente, M. et al. The fallacies of hope: will we discover new antibiotics to combat pathogenic bacteria in time? FEMS Microbiol. Rev. 30, 841–852 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Levy, S. B. & Marshall, B. Antibacterial resistance worldwide: causes, challenges and responses. Nature Med. 10, S122–S129 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Crowley, P. J. & Martini, L. G. Formulation design: new drugs from old. Drug Discov. Today: Therapeutic Strategies 1, 537–542 (2004).

    CAS  Google Scholar 

  7. Projan, S. J. Why is big Pharma getting out of antibacterial drug discovery? Curr. Opin. Microbiol. 6, 427–430 (2003).

    Article  PubMed  Google Scholar 

  8. Fernandes, P. Antibacterial discovery and development — the failure of success? Nature Biotechnol. 24, 1497–1503 (2006).

    Article  CAS  Google Scholar 

  9. Talbot, G. H. et al. Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the infectious diseases society of America. Clin. Infect. Dis. 42, 657–668 (2006).

    Article  PubMed  Google Scholar 

  10. Blount, K. F., Wang, J. X., Lim, J., Sudarsan, N. & Breaker, R. R. Antibacterial lysine analogs that target lysine riboswitches. Nature Chem. Biol. 3, 44–49 (2007). Identified lysine analogues that bind to lysine riboswitches in vitro and inhibit the growth of Bacillus subtilis . Also discusses the general importance of riboswitches and their suitability as antibacterial drug targets.

    Article  CAS  Google Scholar 

  11. Wright, G. D. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Rev. Microbiol. 5, 175–186 (2007).

    Article  CAS  Google Scholar 

  12. Mwangi, M. M. et al. Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc. Natl Acad. Sci. USA 104, 9451–9456 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Finlay, B. B. & Falkow, S. Common themes in microbial pathogenicity revisited. Microbiol. Mol. Biol. Rev. 61, 136–169 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, Y. M., Almqvist, F. & Hultgren, S. J. Targeting virulence for antimicrobial chemotherapy. Curr. Opin. Pharmacol. 3, 513–519 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Marra, A. Can virulence factors be viable antibacterial targets? Expert Rev. Anti. Infect. Ther. 2, 61–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Savage, D. C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).

    Article  CAS  PubMed  Google Scholar 

  17. Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller, J. F., Mekalanos, J. J. & Falkow, S. Coordinate regulation and sensory transduction in the control of bacterial virulence. Science 243, 916–922 (1989). A perspective that emphasizes the need to understand coordinate regulation and sensory transduction to understand the events that occur during the pathogenesis of infectious disease.

    Article  CAS  PubMed  Google Scholar 

  19. Virgin, H. W. In vivo veritas: pathogenesis of infection as it actually happens. Nature Immunol. 8, 1143–1147 (2007). An overview and perspective of the benefits that are ascribed to bridging the disciplines of microbiology and immunology, including lessons from Heisenberg.

    Article  CAS  Google Scholar 

  20. Moxon, E. R., Rainey, P. B., Nowak, M. A. & Lenski, R. E. Adaptive evolution of highly mutable loci in pathogenic bacteria. Curr. Biol. 4, 24–33 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Monack, D. M., Mueller, A. & Falkow, S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nature Rev. Microbiol. 2, 747–765 (2004). Review and consideration of the dynamic cross-talk at the host–pathogen interface and the delicate balance between protective immunity and immunopathology.

    Article  CAS  Google Scholar 

  22. Kaufmann, S. H. E. The contribution of immunology to the rational design of novel antibacterial vaccines. Nature Rev. Microbiol. 5, 491–504 (2007).

    Article  CAS  Google Scholar 

  23. Kokai-Kun, J. F. & Mond, J. J. Antibody therapy for treatment or prevention of infectious diseases. Drug Discov. Today: Therapeutic Strategies 1, 475–481 (2004).

    CAS  Google Scholar 

  24. Pirofski, L. A. & Casadevall, A. Immunomodulators as an antimicrobial tool. Curr. Opin. Microbiol. 9, 489–495 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hung, D. L. & Hultgren, S. J. Pilus biogenesis via the chaperone/usher pathway: an integration of structure and function. J. Struct. Biol. 124, 201–220 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Telford, J. L., Barocchi, M. le A., Margarit, I., Rappuoli, R. & Grandi, G. Pili in Gram-positive pathogens. Nature Rev. Microbiol. 4, 509–519 (2006).

    Article  CAS  Google Scholar 

  27. Barocchi, M. A. et al. A pneumococcal pilus influences virulence and host inflammatory responses. Proc. Natl Acad. Sci. USA 103, 2857–2862 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mulvey, M. A. Adhesion and entry of uropathogenic Escherichia coli. Cell. Microbiol. 4, 257–271 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Garofalo, C. K. et al. Escherichia coli from urine of female patients with urinary tract infections is competent for intracellular bacterial community formation. Infect. Immun. 75, 52–60 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Martinez, J. J., Mulvey, M. A., Schilling, J. D., Pinkner, J. S. & Hultgren, S. J. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J. 19, 2803–2812 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sauer, F. G., Mulvey, M. A., Schilling, J. D., Martinez, J. J. & Hultgren, S. J. Bacterial pili: molecular mechanisms of pathogenesis. Curr. Opin. Microbiol. 3, 65–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Anderson, G. G. et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301, 105–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Justice, S. S. et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Natl Acad. Sci. USA 101, 1333–1338 (2004). Revealed the multi-step E. coli pathogenic cascade using time-lapse fluorescence videomicroscopy to observe infected mouse-bladder explants.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rosen Da, H. T., Stamm W. E., Humphrey, P. A. & Hultgren, S. J. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. (in the press).

  35. Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Mysorekar, I. U. & Hultgren, S. J. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc. Natl Acad. Sci. USA 103, 14170–14175 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wright, K. J., Seed, P. C. & Hultgren, S. J. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell. Microbiol. 9, 2230–2241 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Kihlberg, J. & Magnusson, G. Use of carbohydrates and peptides in studies of adhesion of pathogenic bacteria and in efforts to generate carbohydrate-specific T cells. Pure Appl. Chem. 68, 2119–2128 (1996).

    Article  CAS  Google Scholar 

  39. 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. 55, 472–476 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bouckaert, J. et al. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol. Microbiol. 55, 441–455 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Sauer, F. G., Remaut, H., Hultgren, S. J. & Waksman, G. Fiber assembly by the chaperone–usher pathway. Biochim. Biophys. Acta 1694, 259–267 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Chen, S. L. et al. Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach. Proc. Natl Acad. Sci. USA 103, 5977–5982 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Svensson, A. et al. Design and evaluation of pilicides: potential novel antibacterial agents directed against uropathogenic Escherichia coli. Chembiochem 2, 915–918 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Larsson, A. et al. Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein–protein interactions in uropathogenic Escherichia coli. J. Med. Chem. 48, 935–945 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Pinkner, J. S. et al. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc. Natl Acad. Sci. USA 103, 17897–17902 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Report No. 04–5512, 153–183 (US Government Printing Office, Washington DC, 2004).

  47. Report No. 04–5512, 187–209 (US Government Printing Office, Washington DC, 2004).

  48. Ronald, A. R. et al. Urinary tract infection in adults: research priorities and strategies. Int. J. Antimicrob. Agents 17, 343–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Acharya, V. N. Urinary tract infection — a dangerous and unrecognised forerunner of systemic sepsis. J. Postgrad. Med. 38, 52–54 (1992).

    CAS  PubMed  Google Scholar 

  50. Schmitt, C. K., Meysick, K. C. & O'Brien, A. D. Bacterial toxins: friends or foes? Emerg. Infect. Dis. 5, 224–234 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Spangler, B. D. Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol. Rev. 56, 622–647 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hung, D. T., Shakhnovich, E. A., Pierson, E. & Mekalanos, J. J. Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science 310, 670–674 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Keller, M. A. & Stiehm, E. R. Passive immunity in prevention and treatment of infectious diseases. Clin. Microbiol. Rev. 13, 602–614 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Arnon, S. S., Schechter, R., Maslanka, S. E., Jewell, N. P. & Hatheway, C. L. Human botulism immune globulin for the treatment of infant botulism. N. Engl. J. Med. 354, 462–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Young, J. A. & Collier, R. J. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 76, 243–265 (2007). Describes the structural basis and molecular mechanisms of the anthrax toxin and provides insight into toxin function.

    Article  CAS  PubMed  Google Scholar 

  56. Saenz, J. B., Doggett, T. A. & Haslam, D. B. Identification and characterization of small molecules that inhibit intracellular toxin transport. Infect. Immun. 75, 4552–4561 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhao, L. & Haslam, D. B. A quantitative and highly sensitive luciferase-based assay for bacterial toxins that inhibit protein synthesis. J. Med. Microbiol. 54, 1023–1030 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Tonello, F., Seveso, M., Marin, O., Mock, M. & Montecucco, C. Screening inhibitors of anthrax lethal factor. Nature 418, 386 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Panchal, R. G. et al. Identification of small molecule inhibitors of anthrax lethal factor. Nature Struct. Mol. Biol. 11, 67–72 (2004).

    Article  CAS  Google Scholar 

  60. Turk, B. E. et al. The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nature Struct. Mol. Biol. 11, 60–66 (2004).

    Article  CAS  Google Scholar 

  61. Russell, P. K. Project BioShield: what it is, why it is needed, and its accomplishments so far. Clin. Infect. Dis. 45, S68–S72 (2007).

    Article  PubMed  Google Scholar 

  62. US Securities and Exchange Commission (SEC). Pharmathene, Inc. Form 10-Q, Quarter Ended September 30, Commission File Number 001-32587. SEC web site [online], (2007).

  63. Food and Drug Administration Center for Drug Evaluation and Research. Summary Minutes of the Anti-Infective Drugs Advisory Committee on April 12, 2007 [online], (2007).

  64. Gyles, C. L. Shiga toxin-producing Escherichia coli: an overview. J. Anim. Sci. 85, E45–E62 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Sandkvist, M. et al. General secretion pathway (eps) genes required for toxin secretion and outer membrane biogenesis in Vibrio cholerae. J. Bacteriol. 179, 6994–7003 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cornelis, G. R. The type III secretion injectisome. Nature Rev. Microbiol. 4, 811–825 (2006).

    Article  CAS  Google Scholar 

  67. Cornelis, G. R. & Wolf-Watz, H. The Yersinia Yop virulon: a bacterial system for subverting eukaryotic cells. Mol. Microbiol. 23, 861–867 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Cornelis, G. R. Yersinia type III secretion: send in the effectors. J. Cell. Biol. 158, 401–408 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cornelis, G. R. & Van Gijsegem, F. Assembly and function of type III secretory systems. Annu. Rev. Microbiol. 54, 735–774 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Rosqvist, R., Hakansson, S., Forsberg, A. & Wolf-Watz, H. Functional conservation of the secretion and translocation machinery for virulence proteins of yersiniae, salmonellae and shigellae. EMBO J. 14, 4187–4195 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kauppi, A. M., Nordfelth, R., Uvell, H., Wolf-Watz, H. & Elofsson, M. Targeting bacterial virulence: inhibitors of type III secretion in Yersinia. Chem. Biol. 10, 241–249 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Nordfelth, R., Kauppi, A. M., Norberg, H. A., Wolf-Watz, H. & Elofsson, M. Small-molecule inhibitors specifically targeting type III secretion. Infect. Immun. 73, 3104–3114 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wolf, K. et al. Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle. Mol. Microbiol. 61, 1543–1555 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Muschiol, S. et al. A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis. Proc. Natl Acad. Sci. USA 103, 14566–14571 (2006). An elegant application of chemical genetics to microbial pathogenesis. A small molecule that was identified as a T3SS inhibitor in Yersinia spp. inhibited virulence of C. trachomatis , which supports the notion that the T3SS is important in C. trachomatis pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bailey, L. et al. Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle. FEBS Lett. 581, 587–595 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Saye, D. E. Recurring and antimicrobial-resistant infections: considering the potential role of biofilms in clinical practice. Ostomy Wound Manage. 53, 46–62 (2007).

    PubMed  Google Scholar 

  77. Hall-Stoodley, L. et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 296, 202–211 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Carron, M. A., Tran, V. R., Sugawa, C. & Coticchia, J. M. Identification of Helicobacter pylori biofilms in human gastric mucosa. J. Gastrointest. Surg. 10, 712–717 (2006).

    Article  PubMed  Google Scholar 

  79. Lam, J., Chan, R., Lam, K. & Costerton, J. W. Production of mucoid microcolonies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect. Immun. 28, 546–556 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Singh, P. K. et al. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407, 762–764 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Benghezal, M. et al. Inhibitors of bacterial virulence identified in a surrogate host model. Cell. Microbiol. 9, 1336–1342 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Keller, L. & Surette, M. G. Communication in bacteria: an ecological and evolutionary perspective. Nature Rev. Microbiol. 4, 249–258 (2006). A holistic perspective of the potential roles of QS signals, from a cooperative to the battleground.

    Article  CAS  Google Scholar 

  83. Bassler, B. L. & Losick, R. Bacterially speaking. Cell 125, 237–246 (2006). A creative composition and a lively review of the business of bacterial communication.

    Article  CAS  PubMed  Google Scholar 

  84. Kjelleberg, S. et al. Do marine natural products interfere with prokaryotic AHL regulatory systems? Aquat. Microb. Ecol. 13, 85–93 (1997).

    Article  Google Scholar 

  85. Manefield, M. et al. Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein [in process citation]. Microbiology 145, 283–291 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Higgins, D. A. et al. The major Vibrio cholerae autoinducer and its role in virulence factor production. Nature 14 Nov 2007 (doi:10.1038/nature06284).

    Article  CAS  PubMed  Google Scholar 

  87. Hentzer, M. et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J. 22, 3803–3815 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bjarnsholt, T. & Givskov, M. Quorum-sensing blockade as a strategy for enhancing host defences against bacterial pathogens. Phil. Trans. R. Soc. Lond. B 362, 1213–1222 (2007).

    Article  CAS  Google Scholar 

  89. Geske, G. D., O'Neill, J. C. & Blackwell, H. E. N-phenylacetanoyl-L-homoserine lactones can strongly antagonize or superagonize quorum sensing in Vibrio fischeri. ACS Chem. Biol. 2, 315–319 (2007). Identified a non-native N -acylated- L -homoserine lactone that can either inhibit or strongly induce QS in the marine symbiont V. fischeri , depending on the molecule concentration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Miller, M. B., Skorupski, K., Lenz, D. H., Taylor, R. K. & Bassler, B. L. Parallel quorum sensing systems converge to regulate virulence in Vibrio cholerae. Cell 110, 303–314 (2002). Revealed the redundant QS capacity in V. cholerae and discusses implications in terms of V. choler ae pathogenicity.

    Article  CAS  PubMed  Google Scholar 

  91. Wadhams, G. H. & Armitage, J. P. Making sense of it all: bacterial chemotaxis. Nature Rev. Mol. Cell Biol. 5, 1024–1037 (2004).

    Article  CAS  Google Scholar 

  92. Galperin, M. Y. Structural classification of bacterial response regulators: diversity of output domains and domain combinations. J. Bacteriol. 188, 4169–4182 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ulrich, L. E. & Zhulin, I. B. MiST: a microbial signal transduction database. Nucleic Acids Res. 35, D386–D390 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Mascher, T., Helmann, J. D. & Unden, G. Stimulus perception in bacterial signal-transducing histidine kinases. Microbiol. Mol. Biol. Rev. 70, 910–938 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Barrett, J. F. & Hoch, J. A. Two-component signal transduction as a target for microbial anti-infective therapy. Antimicrob. Agents Chemother. 42, 1529–1536 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mayville, P. et al. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc. Natl Acad. Sci. USA 96, 1218–1223 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Otto, M. Quorum-sensing control in Staphylococci — a target for antimicrobial drug therapy? FEMS Microbiol. Lett. 241, 135–141 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Arthur, M., Molinas, C. & Courvalin, P. The VanS–VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J. Bacteriol. 174, 2582–2591 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Evers, S. & Courvalin, P. Regulation of VanB-type vancomycin resistance gene expression by the VanS(B)–VanR (B) two-component regulatory system in Enterococcus faecalis V583. J. Bacteriol. 178, 1302–1309 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sintchenko, V., Iredell, J. R. & Gilbert, G. L. Pathogen profiling for disease management and surveillance. Nature Rev. Microbiol. 5, 464–470 (2007).

    Article  CAS  Google Scholar 

  101. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. Drug Discov. 6, 29–40 (2007).

    Article  CAS  Google Scholar 

  102. Jones, C. H. et al. FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae. Proc. Natl Acad. Sci. USA 92, 2081–2085 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge funding from the National Institutes of Health to S.J.H. (grant numbers P50-ORWH/DK64540, R01AI029549, R01AI048689 and R01DK51406), G.R.M. (grant number R01GM068460) and L.C. (grant number T32A107172).

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Correspondence to Scott J. Hultgren.

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Gary R. Eldridge is President and Chief Executive Officer of Sequoia Sciences, Missouri, USA.

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DATABASES

Entrez Genome Project

Bacillus anthracis

Chlamydia trachomatis

Clostridium botulinum

Escherichia coli

Haemophilus influenzae

Helicobacter pylori

Pseudomonas aeruginosa

Shigella dysenteriae

Shigella flexneri

Staphylococcus aureus

Streptococcus pneumoniae

Vibrio cholerae

Vibrio fischeri

Yersinia pestis

Yersinia pseudotuberculosis

FURTHER INFORMATION

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Glossary

Riboswitch

An mRNA control element that changes conformation in response to the binding of a metabolite (for example, glycine, lysine and coenzyme B12) and influences gene expression.

Microbiota

The entire collection of microorganisms (bacteria, archaea, fungi, sometimes protozoa and viruses) that are resident on or in the host.

Pilus

A non-flagellar filamentous appendage that is formed on the surface of many bacteria.

Quorum sensing

(QS). The process by which bacteria use signalling molecules to monitor bacterial density and coordinate gene expression in a population-density-dependent manner.

Adhesin

The surface-exposed bacterial molecule that mediates specific binding to a receptor or ligand on a target cell.

Autotransporter

A large family of secreted proteins in Gram-negative bacteria that harbour three functional domains — the amino-terminal signal peptide, the secreted mature protein (passenger domain) and a carboxy-terminal translocator domain — to allow secretion of the passenger protein.

Biofilm

A community of cells that are attached to a surface or interface or to each other, and are imbedded in a self-made, protective matrix of extracellular polymeric substances.

Chaperone–usher system

A system that facilitates the folding, transport and ordered assembly of pilus subunits at the cell surface.

Botulism

A rare, but serious illness that is caused by a nerve toxin, botulinum, that is produced by the bacterium Clostridium botulinum.

Chemical genetics

The strategy of using small molecules to alter and interrogate biological processes. The small-molecule tools of dissection in this approach harbour the precious chemical scaffolds that may lead directly to new therapeutics.

Project BioShield

The Project BioShield Act was incorporated into law by the United States government in July 2004. Through Project BioShield, $5.6 billion will be invested by 2013 in the development of new technological and therapeutic countermeasures against potential bioterrorism agents and to purchase and stockpile effective therapeutics to prevent and treat the illnesses that are related to these threats.

Haemolytic uraemic syndrome

A disease that primarily affects infants and children and is characterized by the loss and destruction of red blood cells. Occurs most commonly in children after a gastrointestinal infection or upper respiratory-tract infection and can lead to kidney failure.

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Cegelski, L., Marshall, G., Eldridge, G. et al. The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6, 17–27 (2008). https://doi.org/10.1038/nrmicro1818

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