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Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation

Nature Chemical Biology volume 3, pages 549–556 (2007)Cite this article

Abstract

Antibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed to keep pace with the evolution of this resistance, which suggests that new strategies to combat bacterial infections may be required. An improved understanding of bacterial stress responses and evolution suggests that in some circumstances, the ability of bacteria to survive antibiotic therapy either by transiently tolerating antibiotics or by evolving resistance requires specific biochemical processes that may themselves be subject to intervention. Inhibiting these processes may prolong the efficacy of current antibiotics and provide an alternative to escalating the current arms race between antibiotics and bacterial resistance. Though these approaches are not clinically validated and will certainly face their own set of challenges, their potential to protect our ever-shrinking arsenal of antibiotics merits their investigation. This Review summarizes the early efforts toward this goal.

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Figure 1: Emergence of mutation-mediated resistance.
Figure 2: Horizontal transfer of resistance and virulence factors.
Figure 3: Tolerance of antimicrobial therapy.

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References

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

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rice, L.B. Antimicrobial resistance in gram-positive bacteria. Am. J. Infect. Control 34 (suppl. 1), S11–19; discussion S64–73 (2006).

    Article  PubMed  Google Scholar 

  3. Wright, A. et al. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004. MMWR Morb. Mortal. Wkly. Rep. 55, 301–305 (2006).

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. 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 

  6. Jin, D.J. & Gross, C.A. Mapping and sequencing of mutations in the Escherichia coli rpoB gene that lead to rifampicin resistance. J. Mol. Biol. 202, 45–58 (1988).

    Article  PubMed  CAS  Google Scholar 

  7. Drlica, K. & Zhao, X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev. 61, 377–392 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zhang, Y. & Young, D. Molecular genetics of drug resistance in Mycobacterium tuberculosis. J. Antimicrob. Chemother. 34, 313–319 (1994).

    Article  PubMed  CAS  Google Scholar 

  9. Woodford, N. & Ellington, M.J. The emergence of antibiotic resistance by mutation. Clin. Microbiol. Infect. 13, 5–18 (2007).

    Article  PubMed  CAS  Google Scholar 

  10. Miller, J.H. Spontaneous mutators in bacteria: insights into pathways of mutagenesis and repair. Annu. Rev. Microbiol. 50, 625–643 (1996).

    Article  PubMed  CAS  Google Scholar 

  11. Cirz, R.T. & Romesberg, F.E. Induction and inhibition of ciprofloxacin resistance-conferring mutations in hypermutator bacteria. Antimicrob. Agents Chemother. 50, 220–225 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. LeClerc, J.E., Li, B., Payne, W.L. & Cebula, T.A. High mutation frequencies among Escherichia coli and Salmonella pathogens. Science 274, 1208–1211 (1996).

    Article  PubMed  CAS  Google Scholar 

  13. Oliver, A., Canton, R., Campo, P., Baquero, F. & Blazquez, J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 288, 1251–1254 (2000).

    Article  PubMed  CAS  Google Scholar 

  14. Montanari, S. et al. Biological cost of hypermutation in Pseudomonas aeruginosa strains from patients with cystic fibrosis. Microbiology 153, 1445–1454 (2007).

    Article  PubMed  CAS  Google Scholar 

  15. Funchain, P. et al. The consequences of growth of a mutator strain of Escherichia coli as measured by loss of function among multiple gene targets and loss of fitness. Genetics 154, 959–970 (2000).

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Giraud, A. et al. Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut. Science 291, 2606–2608 (2001).

    Article  PubMed  CAS  Google Scholar 

  17. Harris, R.S., Longerich, S. & Rosenberg, S.M. Recombination in adaptive mutation. Science 264, 258–260 (1994).

    Article  PubMed  CAS  Google Scholar 

  18. Cairns, J. & Foster, P.L. Adaptive reversion of a frameshift mutation in Escherichia coli. Genetics 128, 695–701 (1991).

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Foster, P.L., Trimarchi, J.M. & Maurer, R.A. Two enzymes, both of which process recombination intermediates, have opposite effects on adaptive mutation in Escherichia coli. Genetics 142, 25–37 (1996).

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Harris, R.S., Ross, K.J. & Rosenberg, S.M. Opposing roles of the holliday junction processing systems of Escherichia coli in recombination-dependent adaptive mutation. Genetics 142, 681–691 (1996).

    PubMed  PubMed Central  CAS  Google Scholar 

  21. McKenzie, G.J., Lombardo, M.J. & Rosenberg, S.M. Recombination-dependent mutation in Escherichia coli occurs in stationary phase. Genetics 149, 1163–1165 (1998).

    PubMed  PubMed Central  CAS  Google Scholar 

  22. McKenzie, G.J., Harris, R.S., Lee, P.L. & Rosenberg, S.M. The SOS response regulates adaptive mutation. Proc. Natl. Acad. Sci. USA 97, 6646–6651 (2000).

    Article  PubMed  CAS  Google Scholar 

  23. Cirz, R.T. et al. Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol. 3, e176 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Miller, C. et al. SOS response induction by beta-lactams and bacterial defense against antibiotic lethality. Science 305, 1629–1631 (2004).

    Article  PubMed  CAS  Google Scholar 

  25. Riesenfeld, C., Everett, M., Piddock, L.J. & Hall, B.G. Adaptive mutations produce resistance to ciprofloxacin. Antimicrob. Agents Chemother. 41, 2059–2060 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Alonso, A., Campanario, E. & Martinez, J.L. Emergence of multidrug-resistant mutants is increased under antibiotic selective pressure in Pseudomonas aeruginosa. Microbiology 145, 2857–2862 (1999).

    Article  PubMed  CAS  Google Scholar 

  27. Boshoff, H.I., Reed, M.B., Barry, C.E. III & Mizrahi, V. DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Cell 113, 183–193 (2003).

    Article  PubMed  CAS  Google Scholar 

  28. Taddei, F. et al. Role of mutator alleles in adaptive evolution. Nature 387, 700–702 (1997).

    Article  PubMed  CAS  Google Scholar 

  29. Joo, L.M., Macfarlane-Smith, L.R. & Okeke, I.N. Error-prone DNA repair system in enteroaggregative Escherichia coli identified by subtractive hybridization. J. Bacteriol. 189, 3793–3803 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Bilello, J.A., Bauer, G., Dudley, M.N., Cole, G.A. & Drusano, G.L. Effect of 2′,3′-didehydro-3′-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies. Antimicrob. Agents Chemother. 38, 1386–1391 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Paterson, D.L. & Bonomo, R.A. Extended-spectrum beta-lactamases: a clinical update. Clin. Microbiol. Rev. 18, 657–686 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Weigel, L.M. et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 302, 1569–1571 (2003).

    Article  PubMed  CAS  Google Scholar 

  33. Fosheim, G.E., Carey, R.B. & Limbago, B.M. Evaluation of the AdvanDx VRE EVIGENE assay for detection of vanA in vancomycin-resistant Staphylococcus aureus. J. Clin. Microbiol. 45, 1611–1613 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cao, T.B. & Saier, M.H. Jr. Conjugal type IV macromolecular transfer systems of Gram-negative bacteria: organismal distribution, structural constraints and evolutionary conclusions. Microbiology 147, 3201–3214 (2001).

    Article  PubMed  CAS  Google Scholar 

  35. Cascales, E. & Christie, P.J. Definition of a bacterial type IV secretion pathway for a DNA substrate. Science 304, 1170–1173 (2004).

    Article  PubMed  CAS  Google Scholar 

  36. Yeo, H.J. & Waksman, G. Unveiling molecular scaffolds of the type IV secretion system. J. Bacteriol. 186, 1919–1926 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Frost, L.S., Leplae, R., Summers, A.O. & Toussaint, A. Mobile genetic elements: the agents of open source evolution. Nat. Rev. Microbiol. 3, 722–732 (2005).

    Article  PubMed  CAS  Google Scholar 

  38. Hilleringmann, M. et al. Inhibitors of Helicobacter pylori ATPase Cagα block CagA transport and cag virulence. Microbiology 152, 2919–2930 (2006).

    Article  PubMed  CAS  Google Scholar 

  39. Backert, S. et al. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell. Microbiol. 2, 155–164 (2000).

    Article  PubMed  CAS  Google Scholar 

  40. Odenbreit, S. et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287, 1497–1500 (2000).

    Article  PubMed  CAS  Google Scholar 

  41. Grohmann, E., Muth, G. & Espinosa, M. Conjugative plasmid transfer in gram-positive bacteria. Microbiol. Mol. Biol. Rev. 67, 277–301 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Chen, I. & Dubnau, D. DNA uptake during bacterial transformation. Nat. Rev. Microbiol. 2, 241–249 (2004).

    Article  PubMed  CAS  Google Scholar 

  43. Fernandez-Lopez, R. et al. Unsaturated fatty acids are inhibitors of bacterial conjugation. Microbiology 151, 3517–3526 (2005).

    Article  PubMed  CAS  Google Scholar 

  44. Hurdle, J.G., O'Neill, A.J., Mody, L., Chopra, I. & Bradley, S.F. In vivo transfer of high-level mupirocin resistance from Staphylococcus epidermidis to methicillin-resistant Staphylococcus aureus associated with failure of mupirocin prophylaxis. J. Antimicrob. Chemother. 56, 1166–1168 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Beaber, J.W., Hochhut, B. & Waldor, M.K. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427, 72–74 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. Moritz, E.M. & Hergenrother, P.J. Toxin-antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci. Proc. Natl. Acad. Sci. USA 104, 311–316 (2007).

    Article  PubMed  CAS  Google Scholar 

  47. Engelberg-Kulka, H., Sat, B., Reches, M., Amitai, S. & Hazan, R. Bacterial programmed cell death systems as targets for antibiotics. Trends Microbiol. 12, 66–71 (2004).

    Article  PubMed  CAS  Google Scholar 

  48. Gerdes, K., Christensen, S.K. & Lobner-Olesen, A. Prokaryotic toxin-antitoxin stress response loci. Nat. Rev. Microbiol. 3, 371–382 (2005).

    Article  PubMed  CAS  Google Scholar 

  49. Gamage, S.D., Strasser, J.E., Chalk, C.L. & Weiss, A.A. Nonpathogenic Escherichia coli can contribute to the production of Shiga toxin. Infect. Immun. 71, 3107–3115 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Fuchs, S. et al. Influence of RecA on in vivo virulence and Shiga toxin 2 production in Escherichia coli pathogens. Microb. Pathog. 27, 13–23 (1999).

    Article  PubMed  CAS  Google Scholar 

  51. Sumby, P. & Waldor, M.K. Transcription of the toxin genes present within the Staphylococcal phage φSa3ms is intimately linked with the phage's life cycle. J. Bacteriol. 185, 6841–6851 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Hastings, P.J., Rosenberg, S.M. & Slack, A. Antibiotic-induced lateral transfer of antibiotic resistance. Trends Microbiol. 12, 401–404 (2004).

    Article  PubMed  CAS  Google Scholar 

  53. Fish, D.N., Piscitelli, S.C. & Danziger, L.H. Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies. Pharmacotherapy 15, 279–291 (1995).

    PubMed  CAS  Google Scholar 

  54. Hobby, G.L., Meyer, K. & Chaffee, E. Observations on the mechanism of action of penicillin. Proc. Soc. Exp. Biol. Med. 50, 281–285 (1942).

    Article  CAS  Google Scholar 

  55. Keren, I., Shah, D., Spoering, A., Kaldalu, N. & Lewis, K. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 186, 8172–8180 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Wiuff, C. et al. Phenotypic tolerance: antibiotic enrichment of noninherited resistance in bacterial populations. Antimicrob. Agents Chemother. 49, 1483–1494 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Levin, B.R. & Rozen, D.E. Non-inherited antibiotic resistance. Nat. Rev. Microbiol. 4, 556–562 (2006).

    Article  PubMed  CAS  Google Scholar 

  58. Smith, A.L., Fiel, S.B., Mayer-Hamblett, N., Ramsey, B. & Burns, J.L. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 123, 1495–1502 (2003).

    Article  PubMed  CAS  Google Scholar 

  59. Dworzack, D.L., Pugsley, M.P., Sanders, C.C. & Horowitz, E.A. Emergence of resistance in gram-negative bacteria during therapy with expanded-spectrum cephalosporins. Eur. J. Clin. Microbiol. 6, 456–459 (1987).

    Article  PubMed  CAS  Google Scholar 

  60. Tuomanen, E., Durack, D.T. & Tomasz, A. Antibiotic tolerance among clinical isolates of bacteria. Antimicrob. Agents Chemother. 30, 521–527 (1986).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Lewis, K. Persister cells, dormancy and infectious disease. Nat. Rev. Microbiol. 5, 48–56 (2007).

    Article  PubMed  CAS  Google Scholar 

  62. Gilbert, P., Collier, P.J. & Brown, M.R. Influence of growth rate on susceptibility to antimicrobial agents: biofilms, cell cycle, dormancy, and stringent response. Antimicrob. Agents Chemother. 34, 1865–1868 (1990).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Rogers, H.J. The killing of bacteria by cell wall inhibitors. Contrib. Microbiol. Immunol. 1, 117–134 (1973).

    PubMed  CAS  Google Scholar 

  64. Vazquez-Laslop, N., Lee, H. & Neyfakh, A.A. Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J. Bacteriol. 188, 3494–3497 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Shah, D. et al. Persisters: a distinct physiological state of E. coli. BMC Microbiol. 6, 53 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Keren, I., Kaldalu, N., Spoering, A., Wang, Y. & Lewis, K. Persister cells and tolerance to antimicrobials. FEMS Microbiol. Lett. 230, 13–18 (2004).

    Article  PubMed  CAS  Google Scholar 

  67. Moyed, H.S. & Bertrand, K.P. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155, 768–775 (1983).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Falla, T.J. & Chopra, I. Stabilization of Rhizobium symbiosis plasmids. Microbiology 145, 515–516 (1999).

    Article  PubMed  CAS  Google Scholar 

  69. Buts, L., Lah, J., Dao-Thi, M.H., Wyns, L. & Loris, R. Toxin-antitoxin modules as bacterial metabolic stress managers. Trends Biochem. Sci. 30, 672–679 (2005).

    Article  PubMed  CAS  Google Scholar 

  70. Pedersen, K. et al. The bacterial toxin RelE displays codon-specific cleavage of mRNAs in the ribosomal A site. Cell 112, 131–140 (2003).

    Article  PubMed  CAS  Google Scholar 

  71. Christensen, S.K., Pedersen, K., Hansen, F.G. & Gerdes, K. Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA. J. Mol. Biol. 332, 809–819 (2003).

    Article  PubMed  CAS  Google Scholar 

  72. Pandey, D.P. & Gerdes, K. Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res. 33, 966–976 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Pedersen, K., Christensen, S.K. & Gerdes, K. Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol. Microbiol. 45, 501–510 (2002).

    Article  PubMed  CAS  Google Scholar 

  74. Black, D.S., Irwin, B. & Moyed, H.S. Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J. Bacteriol. 176, 4081–4091 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Korch, S.B., Henderson, T.A. & Hill, T.M. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol. Microbiol. 50, 1199–1213 (2003).

    Article  PubMed  CAS  Google Scholar 

  76. Li, Y. & Zhang, Y. PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob. Agents Chemother. 51, 2092–2099 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Tsilibaris, V., Maenhaut-Michel, G., Mine, N. & Van Melderen, L. What is the benefit for E. coli to have multiple toxin-antitoxin systems in their genomes? J. Bacteriol., published online 18 May 2007 (doi:10.1128/JB.00527-07).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Korch, S.B. & Hill, T.M. Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation. J. Bacteriol. 188, 3826–3836 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Correia, F.F. et al. Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli. J. Bacteriol. 188, 8360–8367 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Spoering, A.L., Vulic, M. & Lewis, K. GlpD and PlsB participate in persister cell formation in Escherichia coli. J. Bacteriol. 188, 5136–5144 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Young, D., Hussell, T. & Dougan, G. Chronic bacterial infections: living with unwanted guests. Nat. Immunol. 3, 1026–1032 (2002).

    Article  PubMed  CAS  Google Scholar 

  82. Coates, A., Hu, Y., Bax, R. & Page, C. The future challenges facing the development of new antimicrobial drugs. Nat. Rev. Drug Discov. 1, 895–910 (2002).

    Article  PubMed  CAS  Google Scholar 

  83. Smith, I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin. Microbiol. Rev. 16, 463–496 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Fritz, C., Maass, S., Kreft, A. & Bange, F.C. Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific. Infect. Immun. 70, 286–291 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. McKinney, J.D. et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735–738 (2000).

    Article  PubMed  CAS  Google Scholar 

  86. Fang, F.C., Libby, S.J., Castor, M.E. & Fung, A.M. Isocitrate lyase (AceA) is required for Salmonella persistence but not for acute lethal infection in mice. Infect. Immun. 73, 2547–2549 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Palmer, K.L., Brown, S.A. & Whiteley, M. Membrane-bound nitrate reductase is required for anaerobic growth in cystic fibrosis sputum. J. Bacteriol. 189, 4449–4455 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Cho, S.H. et al. Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 51, 1380–1385 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Smith, E.E. et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc. Natl. Acad. Sci. USA 103, 8487–8492 (2006).

    Article  PubMed  CAS  Google Scholar 

  90. 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  PubMed  CAS  Google Scholar 

  91. Perez-Capilla, T. et al. SOS-independent induction of dinB transcription by beta-lactam-mediated inhibition of cell wall synthesis in Escherichia coli. J. Bacteriol. 187, 1515–1518 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Roy-Burman, A. et al. Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections. J. Infect. Dis. 183, 1767–1774 (2001).

    Article  PubMed  CAS  Google Scholar 

  93. Jain, M. et al. Type III secretion phenotypes of Pseudomonas aeruginosa strains change during infection of individuals with cystic fibrosis. J. Clin. Microbiol. 42, 5229–5237 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Skinner, J.A., Pilione, M.R., Shen, H., Harvill, E.T. & Yuk, M.H. Bordetella type III secretion modulates dendritic cell migration resulting in immunosuppression and bacterial persistence. J. Immunol. 175, 4647–4652 (2005).

    Article  PubMed  CAS  Google Scholar 

  95. Troisfontaines, P. & Cornelis, G.R. Type III secretion: more systems than you think. Physiology (Bethesda) 20, 326–339 (2005).

    CAS  Google Scholar 

  96. Silver, L.L. Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 6, 41–55 (2007).

    Article  PubMed  CAS  Google Scholar 

  97. Gentry, D.R. et al. Variable sensitivity to bacterial methionyl-tRNA synthetase inhibitors reveals subpopulations of Streptococcus pneumoniae with two distinct methionyl-tRNA synthetase genes. Antimicrob. Agents Chemother. 47, 1784–1789 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Heath, R.J. & Rock, C.O. A triclosan-resistant bacterial enzyme. Nature 406, 145–146 (2000).

    Article  PubMed  CAS  Google Scholar 

  99. Frank, A.C., Alsmark, C.M., Thollesson, M. & Andersson, S.G. Functional divergence and horizontal transfer of type IV secretion systems. Mol. Biol. Evol. 22, 1325–1336 (2005).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the US Office of Naval Research (grant N00014-03-1-0126 to F.E.R.) and Achaogen, Inc.

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    Peter A Smith & Floyd E Romesberg

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Smith, P., Romesberg, F. Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation. Nat Chem Biol 3, 549–556 (2007). https://doi.org/10.1038/nchembio.2007.27

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