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Targeting virulence: can we make evolution-proof drugs?


Antivirulence drugs are a new type of therapeutic drug that target virulence factors, potentially revitalising the drug-development pipeline with new targets. As antivirulence drugs disarm the pathogen, rather than kill or halt pathogen growth, it has been hypothesized that they will generate much weaker selection for resistance than traditional antibiotics. However, recent studies have shown that mechanisms of resistance to antivirulence drugs exist, seemingly damaging the 'evolution-proof' claim. In this Opinion article, we highlight a crucial distinction between whether resistance can emerge and whether it will spread to a high frequency under drug selection. We argue that selection for resistance can be reduced, or even reversed, using appropriate combinations of target and treatment environment, opening a path towards the development of evolutionarily robust novel therapeutics.

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Figure 1: The effects of virulence factors on fitness and virulence in different environments.
Figure 2: Predicted selection on resistance to antivirulence therapeutics.
Figure 3: The mechanistic target of the quorum-sensing inhibitor influences the strength of selection for resistance.


  1. 1

    Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Toprak, E. et al. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nature Genet. 44, 101–105 (2012).

    CAS  Google Scholar 

  3. 3

    D'Costa, V. M. et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011).

    CAS  PubMed  Google Scholar 

  4. 4

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

    CAS  Google Scholar 

  5. 5

    Habets, M. G. J. L. & Brockhurst, M. A. Therapeutic antimicrobial peptides may compromise natural immunity. Biol. Lett. 8, 416–418 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Lipsitch, M. & Samore, M. H. Antimicrobial use and antimicrobial resistance: a population perspective. Emerg. Infect. Dis. 8, 347–354 (2002).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Andersson, D. I. & Hughes, D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Rev. Microbiol. 8, 260–271 (2010).

    CAS  Google Scholar 

  8. 8

    Schrag, S. J. & Perrot, V. Reducing antibiotic resistance. Nature 381, 120–121 (1996).

    CAS  PubMed  Google Scholar 

  9. 9

    Levin, B. R., Perrot, V. & Walker, N. Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. Genetics 154, 985–997 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Coates, A. R. M., Halls, G. & Hu, Y. Novel classes of antibiotics or more of the same? Br. J. Pharmacol. 163, 184–194 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Clatworthy, A. E., Pierson, E. & Hung, D. T. Targeting virulence: a new paradigm for antimicrobial therapy. Nature Chem. Biol. 3, 541–548 (2007).

    CAS  Google Scholar 

  12. 12

    Rasko, D. A. & Sperandio, V. Anti-virulence strategies to combat bacteria-mediated disease. Nature Rev. Drug Discov. 9, 117–128 (2010).

    CAS  Google Scholar 

  13. 13

    García-Contreras, R. et al. Resistance to the quorum-quenching compounds brominated furanone C-30 and 5-fluorouracil in Pseudomonas aeruginosa clinical isolates. Pathog. Dis. 68, 8–11 (2013).

    PubMed  Google Scholar 

  14. 14

    Maeda, T. et al. Quorum quenching quandary: resistance to antivirulence compounds. ISME J. 6, 493–501 (2012).

    CAS  PubMed  Google Scholar 

  15. 15

    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).

    CAS  PubMed  Google Scholar 

  16. 16

    Smith, M. A. et al. Identification of the binding site of Brucella virB8 interaction inhibitors. Chem. Biol. 19, 1041–1048 (2012).

    CAS  PubMed  Google Scholar 

  17. 17

    Defoirdt, T., Boon, N. & Bossier, P. Can bacteria evolve resistance to quorum sensing disruption? PLoS Pathog. 6, e1000989 (2010).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    García-Contreras, R., Maeda, T. & Wood, T. K. Resistance to quorum quenching compounds. Appl. Environ. Microbiol. 79, 6840–6846 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. 19

    Read, A. F., Day, T. & Huijben, S. The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. Proc. Natl Acad. Sci. USA 108, 10871–10877 (2011).

    CAS  PubMed  Google Scholar 

  20. 20

    D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Alizon, S., Hurford, A., Mideo, N. & Van Baalen, M. Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future. J. Evol. Biol. 22, 245–259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Anderson, R. M. & May, R. M. Coevolution of hosts and parasites. Parasitology 85, 411–426 (1982).

    PubMed  Google Scholar 

  23. 23

    Levin, B. R. & Eden, C. S. Selection and evolution of virulence in bacteria — an ecuminical excursion and modest suggestion. Parasitol. 100, S103–S115 (1990).

    Google Scholar 

  24. 24

    Brown, S. P., Cornforth, D. M. & Mideo, N. Evolution of virulence in opportunistic pathogens: generalism, plasticity, and control. Trends Microbiol. 20, 336–342 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Silverstein, S. C. & Steinberg, T. H. in Microbiology 485–505 (J. B. Lippincott, 1990).

    Google Scholar 

  26. 26

    Bae, T. et al. Staphylococcus aureus virulence genes identified by Bursa aurealis mutagenesis and nematode killing. Proc. Natl Acad. Sci. USA 101, 12312–12317 (2004).

    CAS  PubMed  Google Scholar 

  27. 27

    Köhler, C.-D. & Dobrindt, U. What defines extraintestinal pathogenic Escherichia coli? Int. J. Med. Microbiol. 301, 642–647 (2011).

    PubMed  Google Scholar 

  28. 28

    Nowrouzian, F. L., Adlerberth, I. & Wold, A. E. Enhanced persistence in the colonic microbiota of Escherichia coli strains belonging to phylogenetic group B2: role of virulence factors and adherence to colonic cells. Microbes Infect. 8, 834–840 (2006).

    CAS  PubMed  Google Scholar 

  29. 29

    Diard, M. et al. Pathogenicity-associated islands in extraintestinal pathogenic Escherichia coli are fitness elements involved in intestinal colonization. J. Bacteriol. 192, 4885–4893 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Alsam, S. et al. Escherichia coli interactions with Acanthamoeba: a symbiosis with environmental and clinical implications. J. Med. Microbiol. 55, 689–694 (2006).

    PubMed  Google Scholar 

  31. 31

    Gall, T. L. et al. Extraintestinal virulence is a coincidental by-product of commensalism in B2 phylogenetic group Escherichia coli strains. Mol. Biol. Evol. 24, 2373–2384 (2007).

    PubMed  Google Scholar 

  32. 32

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

    CAS  Google Scholar 

  33. 33

    Steinberg, K. M. & Levin, B. R. Grazing protozoa and the evolution of the Escherichia coli O157:H7 Shiga toxin-encoding prophage. Proc. Biol. Sci. 274, 1921–1929 (2007).

    PubMed  Google Scholar 

  34. 34

    Montarry, J., Hamelin, F. M., Glais, I., Corbi, R. & Andrivon, D. Fitness costs associated with unnecessary virulence factors and life history traits: evolutionary insights from the potato late blight pathogen Phytophthora infestans. BMC Evol. Biol. 10, 283 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Wu, H. et al. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J. Antimicrob. Chemother. 53, 1054–1061 (2004).

    CAS  PubMed  Google Scholar 

  36. 36

    Christensen, L. D. et al. Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model. J. Antimicrob. Chemother. 67, 1198–1206 (2012).

    CAS  PubMed  Google Scholar 

  37. 37

    Oogai, Y. et al. Expression of virulence factors by Staphylococcus aureus grown in serum. Appl. Environ. Microbiol. 77, 8097–8105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Genco, C. A. & Dixon, D. W. Emerging strategies in microbial haem capture. Mol. Microbiol. 39, 1–11 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Stecher, B. et al. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    CAS  PubMed  Google Scholar 

  40. 40

    Lysenko, E. S., Lijek, R. S., Brown, S. P. & Weiser, J. N. Within-host competition drives selection for the capsule virulence determinant of Streptococcus pneumoniae. Curr. Biol. 20, 1222–1226 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Levin, B. R. & Bull, J. J. Short-sighted evolution and the virulence of pathogenic microorganisms. Trends Microbiol. 2, 76–81 (1994).

    CAS  PubMed  Google Scholar 

  42. 42

    Liu, C.-I. et al. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319, 1391–1394 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Hall, A. R., Griffiths, V. F., MacLean, R. C. & Colegrave, N. Mutational neighbourhood and mutation supply rate constrain adaptation in Pseudomonas aeruginosa. Proc.Biol. Sci. 277, 643–650 (2010).

    CAS  PubMed  Google Scholar 

  44. 44

    Dyken, J. D. V. & Wade, M. J. The genetic signature of conditional expression. Genetics 184, 557–570 (2010).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Sokurenko, E. V., Gomulkiewicz, R. & Dykhuizen, D. E. Source-sink dynamics of virulence evolution. Nature Rev. Microbiol. 4, 548–555 (2006).

    CAS  Google Scholar 

  46. 46

    Meyers, L. A., Levin, B. R., Richardson, A. R. & Stojiljkovic, I. Epidemiology, hypermutation, within-host evolution and the virulence of Neisseria meningitidis. Proc. Biol. Sci. 270, 1667–1677 (2003).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Nogueira, T., Touchon, M. & Rocha, E. P. C. Rapid evolution of the sequences and gene repertoires of secreted proteins in bacteria. PLoS ONE 7, e49403 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Brown, S. P., Hochberg, M. E. & Grenfell, B. T. Does multiple infection select for raised virulence? Trends Microbiol. 10, 401–405 (2002).

    CAS  PubMed  Google Scholar 

  49. 49

    Buckling, A. et al. Siderophore-mediated cooperation and virulence in Pseudomonas aeruginosa. FEMS Microbiol. Ecol. 62, 135–141 (2007).

    CAS  PubMed  Google Scholar 

  50. 50

    Nogueira, T. et al. Horizontal gene transfer of the secretome drives the evolution of bacterial cooperation and virulence. Curr. Biol. 19, 1683–1691 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Rumbaugh, K. P. et al. Quorum sensing and the social evolution of bacterial virulence. Curr. Biol. 19, 341–345 (2009).

    CAS  PubMed  Google Scholar 

  52. 52

    West, S. A., Diggle, S. P., Buckling, A., Gardner, A. & Griffins, A. S. The social lives of microbes. Annu. Rev. Ecol. Evol. Systemat. 38, 53–77 (2007).

    Google Scholar 

  53. 53

    André, J. & Godelle, B. Multicellular organization in bacteria as a target for drug therapy. Ecol. Lett. 8, 800–810 (2005).

    Google Scholar 

  54. 54

    Griffin, A. S., West, S. A. & Buckling, A. Cooperation and competition in pathogenic bacteria. Nature 430, 1024–1027 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Brown, S. P., West, S. A., Diggle, S. P. & Griffin, A. S. Social evolution in micro-organisms and a Trojan horse approach to medical intervention strategies. Philos. Trans. R. Soc.Lond. B. Biol. Sci. 364, 3157–3168 (2009).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Harrison, F., Browning, L. E., Vos, M. & Buckling, A. Cooperation and virulence in acute Pseudomonas aeruginosa infections. BMC Biol. 4 (2006).

  57. 57

    Mellbye, B. & Schuster, M. The sociomicrobiology of antivirulence drug resistance: a proof of concept. mBio 2, e00131–11 (2011).

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Ross-Gillespie, A., Weigert, M., Brown, S. P. & Kümmerli, R. Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment. Evol. Med. Public Health 1, 18–29 (2014).

    Google Scholar 

  59. 59

    Hamilton, W. Genetical evolution of social behaviour I. J. Theor. Biol. 7, 1–16 (1964).

    CAS  Google Scholar 

  60. 60

    Diggle, S. P., Griffin, A. S., Campbell, G. S. & West, S. A. Cooperation and conflict in quorum-sensing bacterial populations. Nature 450, 411–417 (2007).

    CAS  PubMed  Google Scholar 

  61. 61

    Kümmerli, R., Griffin, A. S., West, S. A., Buckling, A. & Harrison, F. Viscous medium promotes cooperation in the pathogenic bacterium Pseudomonas aeruginosa. Proc. Biol. Sci. 276, 3531–3538 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Grant, A. J. et al. Modelling within-host spatiotemporal dynamics of invasive bacterial disease. PLoS Biol. 6, 757–770 (2008).

    CAS  Google Scholar 

  63. 63

    Willner, D. et al. Spatial distribution of microbial communities in the cystic fibrosis lung. ISME J. 6, 471–474 (2012).

    CAS  Google Scholar 

  64. 64

    Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999).

    CAS  PubMed  Google Scholar 

  65. 65

    Kreft, J. U. Biofilms promote altruism. Microbiology 150, 2751–2760 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Zhu, J. et al. Analogs of the autoinducer 3-oxooctanoyl-homoserine lactone strongly inhibit activity of the traR protein of Agrobacterium tumefaciens. J. Bacteriol. 180, 5398–5405 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Koch, B. et al. The LuxR receptor: the sites of interaction with quorum-sensing signals and inhibitors. Microbiology 151, 3589–3602 (2005).

    CAS  PubMed  Google Scholar 

  68. 68

    Eldar, A. Social conflict drives the evolutionary divergence of quorum sensing. Proc. Natl Acad. Sci. USA 108, 13635–13640 (2011).

    CAS  PubMed  Google Scholar 

  69. 69

    Wright, J. S. et al. The agr radiation: an early event in the evolution of staphylococci. J. Bacteriol. 187, 5585–5594 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Joelsson, A., Liu, Z. & Zhu, J. Genetic and phenotypic diversity of quorum-sensing systems in clinical and environmental isolates of Vibrio cholerae. Infect. Immun. 74, 1141–1147 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Defoirdt, T. et al. The natural furanone (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone disrupts quorum sensing-regulated gene expression in Vibrio harveyi by decreasing the DNA-binding activity of the transcriptional regulator protein luxR. Environ. Microbiol. 9, 2486–2495 (2007).

    CAS  PubMed  Google Scholar 

  72. 72

    Chugani, S. et al. Strain-dependent diversity in the Pseudomonas aeruginosa quorum-sensing regulon. Proc. Natl Acad. Sci. USA 109, E2823–E2831 (2012).

    CAS  PubMed  Google Scholar 

  73. 73

    Dandekar, A. A., Chugani, S. & Greenberg, E. P. Bacterial quorum sensing and metabolic incentives to cooperate. Science 338, 264–266 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Schramm, V. L. et al. Transition state analogues in quorum sensing and SAM recycling. Nucleic Acids Symp. Ser. 52, 75–76 (2008).

    CAS  Google Scholar 

  75. 75

    Park, J. et al. Infection control by antibody disruption of bacterial quorum sensing signaling. Chem. Biol. 14, 1119–1127 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Wilder, C. N., Diggle, S. P. & Schuster, M. Cooperation and cheating in Pseudomonas aeruginosa: the roles of the las, rhl and pqs quorum-sensing systems. ISME J. 5, 1332–1343 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Schuster, M. & Greenberg, E. P. A network of networks: quorum-sensing gene regulation in Pseudomonas aeruginosa. Int. J. Med. Microbiol. 296, 73–81 (2006).

    CAS  PubMed  Google Scholar 

  78. 78

    Schuster, M., Lostroh, C., Ogi, T. & Greenberg, E. P. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis. J. Bacteriol. 185, 2066–2079 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    O'Loughlin, C. T. et al. A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc. Natl Acad. Sci. USA 110, 17981–17986 (2013).

    CAS  PubMed  Google Scholar 

  80. 80

    Vale, P. F., Fenton, A. & Brown, S. P. Limiting damage during infection: lessons from infection tolerance for novel therapeutics. PLoS Biol. 12, e1001769 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Gandon, S., Mackinnon, M. J., Nee, S. & Read, A. F. Imperfect vaccines and the evolution of pathogen virulence. Nature 414, 751–756 (2001).

    CAS  PubMed  Google Scholar 

  82. 82

    Köhler, T., Perron, G. G., Buckling, A. & van Delden, C. Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa. PLoS Pathog. 6, e1000883 (2010).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Soubeyrand, B. & Plotkin, S. A. Microbial evolution — antitoxin vaccines and pathogen virulence. Nature 417, 609–610 (2002).

    CAS  PubMed  Google Scholar 

  84. 84

    Pappenheimer, A. in Bacterial Vaccines (Ed. Germanier, R. ) 1–36 (Academic Press, 1984).

    Google Scholar 

  85. 85

    Gandon, S. & Day, T. Evidences of parasite evolution after vaccination. Vaccine 26, (Suppl. 3), C4–C7 (2008).

    Google Scholar 

  86. 86

    Lowy, I. et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N. Engl. J. Med. 362, 197–205 (2010).

    CAS  PubMed  Google Scholar 

  87. 87

    López, E. L. et al. Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli. Antimicrob. Agents Chemother. 54, 239–243 (2010).

    PubMed  Google Scholar 

  88. 88

    Filippov, A. A. et al. Bacteriophage-resistant mutants in Yersinia pestis: identification of phage receptors and attenuation for mice. PLoS ONE 6, e25486 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Smith, H. W., Huggins, M. B. & Shaw, K. M. The control of experimental Escherichia coli diarrhoea in calves by means of bacteriophages. J. Gen. Microbiol. 133, 1111–1126 (1987).

    CAS  PubMed  Google Scholar 

  90. 90

    Rasmussen, T. B. et al. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J. Bacteriol. 187, 1799–1814 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Felise, H. B. et al. An inhibitor of Gram-negative bacterial virulence protein secretion. Cell Host Microbe 4, 325–336 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Hong, K.-W., Koh, C.-L., Sam, C.-K., Yin, W.-F. & Chan, K.-G. Quorum quenching revisited — from signal decays to signalling confusion. Sensors 12, 4661–4696 (2012).

    PubMed  Google Scholar 

  93. 93

    Chait, R., Craney, A. & Kishony, R. Antibiotic interactions that select against resistance. Nature 446, 668–671 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Fernebro, J. Fighting bacterial infections — future treatment options. Drug Resist. Updat. 14, 125–139 (2011).

    PubMed  Google Scholar 

  95. 95

    Wang, D. et al. Identification of bacterial target proteins for the salicylidene acylhydrazide class of virulence-blocking compounds. J. Biol. Chem. 286, 29922–29931 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Yamagami, S. et al. Efficacy of postinfection treatment with anti-shiga toxin (stx) 2 humanized monoclonal antibody tma-15 in mice lethally challenged with stx-producing Escherichia coli. J. Infect. Dis. 184, 738–742 (2001).

    CAS  PubMed  Google Scholar 

  97. 97

    Dong, Y. H. et al. Quenching quorum-sensing-dependent bacterial infection by an N-acyl homoserine lactonase. Nature 411, 813–817 (2001).

    CAS  PubMed  Google Scholar 

  98. 98

    Hentzer, M. et al. Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 148, 87–102 (2002).

    CAS  PubMed  Google Scholar 

  99. 99

    Rutherford, S. T. & Bassler, B. L. Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb. Perspect. Med. 2, a012427 (2012).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Gilbert, K. B., Kim, T. H., Gupta, R., Greenberg, E. P. & Schuster, M. Global position analysis of the Pseudomonas aeruginosa quorum-sensing transcription factor LasR. Mol. Microbiol. 73, 1072–1085 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Wright, J. S., Jin, R. & Novick, R. P. Transient interference with staphylococcal quorum sensing blocks abscess formation. Proc. Natl Acad. Sci. USA 102, 1691–1696 (2005).

    CAS  PubMed  Google Scholar 

  102. 102

    Papaioannou, E. et al. Quorum-quenching acylase reduces the virulence of Pseudomonas aeruginosa in a Caenorhabditis elegans infection model. Antimicrob. Agents Chemother. 53, 4891–4897 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Smith, J. M. & Harper, D. Animal Signals. (OUP Oxford, 2003).

    Google Scholar 

  104. 104

    Ishida, T. et al. Inhibition of quorum sensing in Pseudomonas aeruginosa by N-acyl cyclopentylamides. Appl. Environ. Microbiol. 73, 3183–3188 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Brackman, G. et al. Structure–activity relationship of cinnamaldehyde analogs as inhibitors of ai-2 based quorum sensing and their effect on virulence of Vibrio spp. PLoS ONE 6, e16084 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Ni, N., Li, M., Wang, J. & Wang, B. Inhibitors and antagonists of bacterial quorum sensing. Med. Res. Rev. 29, 65–124 (2009).

    CAS  PubMed  Google Scholar 

  107. 107

    Kaufmann, G. F. et al. Antibody interference with N-acyl homoserine lactone-mediated bacterial quorum sensing. J. Am. Chem. Soc. 128, 2802–2803 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors thank D. Cornforth, P. Vale, R. Kümmerli, A. Ross-Gillespie, R. Fitzgerald and three anonymous reviewers for comments and discussion. S.P.B. was funded by the Wellcome Trust, UK (grant number WT082273), and the Engineering and Physical Sciences Research Council (EPSRC), UK (grant number EP/H032436/1). S.P.D. was funded by the Royal Society, UK, and the Natural Environment Research Council (NERC), UK (grant number NE/J007064/1). R.C.A. was funded by the Natural Environment Research Council (NERC).

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Allen, R., Popat, R., Diggle, S. et al. Targeting virulence: can we make evolution-proof drugs?. Nat Rev Microbiol 12, 300–308 (2014).

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