Which of the following methods of action would be bacteriostatic?

1. Ehrlich, P. Address in pathology, on chemiotherapy: delivered before the Seventeenth International Congress of Medicine. Br. Med. J. 2, 353–359 (1913).

   CAS  PubMed  PubMed Central  Google Scholar 

2. Wright, G., Hung, D. & Helmann, J. How antibiotics kill bacteria: new models needed? Nat. Med. 19, 544–545 (2013).

   PubMed  Google Scholar 

3. Levin, B. R. et al. A numbers game: ribosome densities, bacterial growth, and antibiotic-mediated stasis and death. mBio 8, e02253-16 (2017).

   CAS  PubMed  PubMed Central  Google Scholar 

4. Mayr, E. Cause and effect in biology. Science 134, 1501–1506 (1961).

   CAS  PubMed  Google Scholar 

5. Laland, K. N., Sterelny, K., Odling-Smee, J., Hoppitt, W. & Uller, T. Cause and effect in biology revisited: is Mayr’s proximate-ultimate dichotomy still useful? Science 334, 1512–1516 (2011).

   CAS  PubMed  Google Scholar 

6. Ariew, A. Ernst Mayr’s ‘ultimate/proximate’ distinction reconsidered and reconstructed. Biol. Philos. 18, 553–565 (2003).

   Google Scholar 

7. Medawar, P. The Uniqueness of the Individual (Methuen, 1957).

8. Venkobachar, C. L. & Rao, A. Mechanism of disinfection: effect of chlorine on cell membrane functions. Water Res. 11, 727–729 (1997).

   Google Scholar 

9. Virto, R., Manas, P., Alvarez, I., Condon, S. & Raso, J. Membrane damage and microbial inactivation by chlorine in the absence and presence of a chlorine-demanding substrate. Appl. Env. Microbiol. 71, 5022–5028 (2005).

   CAS  Google Scholar 

10. Regoes, R. R. et al. Pharmacodynamic functions: a multiparameter approach to the design of antibiotic treatment regimens. Antimicrob. Agents Chemother. 48, 3670–3676 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

11. Southam, C. & Ehrlich, J. Effects of extracts of western redcedar heartwood on certain wood-decaying fungi in culture. Phytopathology 33, 517–524 (1943).

    Google Scholar 

12. Davies, J., Spiegelman, G. B. & Yim, G. The world of subinhibitory antibiotic concentrations. Curr. Opin. Microbiol. 9, 445–453 (2006).

    CAS  PubMed  Google Scholar 

13. Linares, J. F., Gustafsson, I., Baquero, F. & Martinez, J. L. Antibiotics as intermicrobial signaling agents instead of weapons. Proc. Natl Acad. Sci. USA 103, 19484–19489 (2006).

    CAS  PubMed  Google Scholar 

14. Calabrese, E. J. Hormesis: a fundamental concept in biology. Microb. Cell 1, 145–149 (2014).

    PubMed  PubMed Central  Google Scholar 

15. Calabrese, E. J. et al. Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol. Appl. Pharmacol. 222, 122–128 (2007).

    CAS  PubMed  Google Scholar 

16. Udekwu, K. I. & Levin, B. R. Staphylococcus aureus in continuous culture: a tool for the rational design of antibiotic treatment protocols. PLoS ONE 7, e38866 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

17. Bigger, J. W. Treatment of staphylococcal infections with penicillin. Lancet 244, 497–500 (1944).

    Google Scholar 

18. Balaban, N. Q. et al. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 460 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

19. Bailey, E. M., Rybak, M. J. & Kaatz, G. W. Comparative effect of protein binding on the killing activities of teicoplanin and vancomycin. Antimicrob. Agents Chemother. 35, 1089–1092 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

20. Pages, J. M., James, C. E. & Winterhalter, M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat. Rev. Microbiol. 6, 893–903 (2008).

    CAS  PubMed  Google Scholar 

21. Nikaido, H. Multidrug efflux pumps of gram-negative bacteria. J. Bacteriol. 178, 5853–5859 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

22. Poole, K. Efflux-mediated antimicrobial resistance. J. Antimicrob. Chemother. 56, 20–51 (2005).

    CAS  PubMed  Google Scholar 

23. Clarelli, F. et al. Drug-target binding quantitatively predicts optimal antibiotic dose levels. Preprint at bioRxiv https://doi.org/10.1101/369975 (2020).

24. Zhu, J. H. et al. Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription. Nat. Commun. 9, 4218 (2018).

    PubMed  PubMed Central  Google Scholar 

25. Gabrielsson, J., Peletier, L. A. & Hjorth, S. In vivo potency revisited - keep the target in sight. Pharmacol. Ther. 184, 177–188 (2018).

    CAS  PubMed  Google Scholar 

26. Borisova, M., Gisin, J. & Mayer, C. Blocking peptidoglycan recycling in pseudomonas aeruginosa attenuates intrinsic resistance to fosfomycin. Microb. Drug Resist. 20, 231–237 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

28. Jacoby, G. A. AmpC beta-lactamases. Clin. Microbiol. Rev. 22, 161–182 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

29. Mainardi, J. L. et al. Novel mechanism of beta-lactam resistance due to bypass of DD-transpeptidation in Enterococcus faecium. J. Biol. Chem. 275, 16490–16496 (2000).

    CAS  PubMed  Google Scholar 

30. Flensburg, J. & Skold, O. Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim. Eur. J. Biochem. 162, 473–476 (1987).

    CAS  PubMed  Google Scholar 

31. Piddock, L. J. & Walters, R. N. Bactericidal activities of five quinolones for Escherichia coli strains with mutations in genes encoding the SOS response or cell division. Antimicrob. Agents Chemother. 36, 819–825 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

32. Kohanski, M. A., Dwyer, D. J., Hayete, B., Lawrence, C. A. & Collins, J. J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797–810 (2007).

    CAS  PubMed  Google Scholar 

33. Dorr, T., Lewis, K. & Vulic, M. SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet. 5, e1000760 (2009).

    PubMed  PubMed Central  Google Scholar 

34. Hong, Y., Zeng, J., Wang, X., Drlica, K. & Zhao, X. Post-stress bacterial cell death mediated by reactive oxygen species. Proc. Natl Acad. Sci. USA 116, 10064–10071 (2019).

    CAS  PubMed  Google Scholar 

35. McCall, I. C., Shah, N., Govindan, A., Baquero, F. & Levin, B. R. Antibiotic killing of diversely generated populations of nonreplicating bacteria. Antimicrob. Agents Chemother. 63, e02360-18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

36. Peeters, S. H. & de Jonge, M. I. For the greater good: programmed cell death in bacterial communities. Microbiol. Res. 207, 161–169 (2018).

    CAS  PubMed  Google Scholar 

37. Tuomanen, E., Cozens, R., Tosch, W., Zak, O. & Tomasz, A. The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth. J. Gen. Microbiol. 132, 1297–1304 (1986).

    CAS  PubMed  Google Scholar 

38. Vogelman, B. & Craig, W. A. Kinetics of antimicrobial activity. J. Pediatr. 108, 835–840 (1986).

    CAS  PubMed  Google Scholar 

39. Russell, A. D. Mechanisms of antimicrobial action of antiseptics and disinfectants: an increasingly important area of investigation. J. Antimicrob. Chemother. 49, 597–599 (2002).

    CAS  PubMed  Google Scholar 

40. Maillard, J. Y. Bacterial target sites for biocide action. J. Appl. Microbiol. 92, 16S–27S (2002).

    PubMed  Google Scholar 

41. Eliopoulos, G. M. & Eliopoulos, C. T. Antibiotic combinations: should they be tested? Clin. Microbiol. Rev. 1, 139–156 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

42. Chaudhry, W. N. et al. Synergy and order effects of antibiotics and phages in killing pseudomonas aeruginosa biofilms. PLoS ONE 12, e0168615 (2017).

    PubMed  PubMed Central  Google Scholar 

43. Dickey, J. & Perrot, V. Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro. PLoS ONE 14, e0209390 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

44. Morrissey, I. Bactericidal index: a new way to assess quinolone bactericidal activity in vitro. J. Antimicrob. Chemother. 39, 713–717 (1997).

    CAS  PubMed  Google Scholar 

45. Gottardi, W., Klotz, S. & Nagl, M. Superior bactericidal activity of N-bromine compounds compared to their N-chlorine analogues can be reversed under protein load. J. Appl. Microbiol. 116, 1427–1437 (2014).

    CAS  PubMed  Google Scholar 

46. Barry, A. L. et al. Methods for determining bactericidal activity of antimicrobial agents, approved guideline (CLSI, 1999).

47. Yang, J. H., Bening, S. C. & Collins, J. J. Antibiotic efficacy-context matters. Curr. Opin. Microbiol. 39, 73–80 (2017).

    PubMed  PubMed Central  Google Scholar 

48. Epand, R. M., Walker, C., Epand, R. F. & Magarvey, N. A. Molecular mechanisms of membrane targeting antibiotics. Biochim. Biophys. Acta 1858, 980–987 (2016).

    CAS  PubMed  Google Scholar 

49. Harrison, S. T. Bacterial cell disruption: a key unit operation in the recovery of intracellular products. Biotechnol. Adv. 9, 217–240 (1991).

    CAS  PubMed  Google Scholar 

50. Harrison, S. T., Dennis, J. S. & Chase, H. A. in Inhibition and Destruction of the Microbial Cell (ed. Hugo, W. B.) 95–105 (Academic, 1971).

51. Mosser, J. L. & Tomasz, A. Choline-containing teichoic acid as a structural component of pneumococcal cell wall and its role in sensitivity to lysis by an autolytic enzyme. J. Biol. Chem. 245, 287–298 (1970).

    CAS  PubMed  Google Scholar 

52. Garcia, P., Paz Gonzalez, M., Garcia, E., Garcia, J. L. & Lopez, R. The molecular characterization of the first autolytic lysozyme of Streptococcus pneumoniae reveals evolutionary mobile domains. Mol. Microbiol. 33, 128–138 (1999).

    CAS  PubMed  Google Scholar 

53. Rice, K. C. & Bayles, K. W. Molecular control of bacterial death and lysis. Microbiol. Mol. Biol. Rev. 72, 85–109 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

54. Kitano, K. & Tomasz, A. Triggering of autolytic cell wall degradation in Escherichia coli by beta-lactam antibiotics. Antimicrob. Agents Chemother. 16, 838–848 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

55. Shin, J. H. et al. Structural basis of peptidoglycan endopeptidase regulation. Proc. Natl Acad. Sci. USA 117, 11692–11702 (2020).

    CAS  PubMed  Google Scholar 

56. Wecke, J., Perego, M. & Fischer, W. D-Alanine deprivation of Bacillus subtilis teichoic acids is without effect on cell growth and morphology but affects the autolytic activity. Microb. Drug Resist. 2, 123–129 (1996).

    CAS  PubMed  Google Scholar 

57. Silhavy, T. J., Kahne, D. & Walker, S. The bacterial cell envelope. Cold Spring Harb. Perspect. Biol. 2, a000414 (2010).

    PubMed  PubMed Central  Google Scholar 

58. Flores-Kim, J., Dobihal, G. S., Fenton, A., Rudner, D. Z. & Bernhardt, T. G. A switch in surface polymer biogenesis triggers growth-phase-dependent and antibiotic-induced bacteriolysis. eLife 8, e44912 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

59. Bittner, L. M., Arends, J. & Narberhaus, F. When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli. Biol. Chem. 398, 625–635 (2017).

    CAS  PubMed  Google Scholar 

60. Parsons, J. B., Yao, J., Jackson, P., Frank, M. & Rock, C. O. Phosphatidylglycerol homeostasis in glycerol-phosphate auxotrophs of Staphylococcus aureus. BMC Microbiol. 13, 260 (2013).

    PubMed  PubMed Central  Google Scholar 

61. May, K. L. & Silhavy, T. J. Erratum for May and Silhavy, “The Escherichia coli phospholipase PldA regulates outer membrane homeostasis via lipid signaling”. mBio 9, e00718-18 (2018).

    PubMed  PubMed Central  Google Scholar 

62. Yao, Z., Kahne, D. & Kishony, R. Distinct single-cell morphological dynamics under beta-lactam antibiotics. Mol. Cell 48, 705–712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

63. Thomanek, N. et al. Intricate crosstalk between lipopolysaccharide, phospholipid and fatty acid metabolism in Escherichia coli modulates proteolysis of LpxC. Front. Microbiol. 9, 3285 (2018).

    PubMed  Google Scholar 

64. Bernadsky, G., Beveridge, T. J. & Clarke, A. J. Analysis of the sodium dodecyl sulfate-stable peptidoglycan autolysins of select gram-negative pathogens by using renaturing polyacrylamide gel electrophoresis. J. Bacteriol. 176, 5225–5232 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

65. van Heijenoort, J. Peptidoglycan hydrolases of Escherichia coli. Microbiol. Mol. Biol. Rev. 75, 636–663 (2011).

    PubMed  PubMed Central  Google Scholar 

66. Vollmer, W., Joris, B., Charlier, P. & Foster, S. Bacterial peptidoglycan (murein) hydrolases. FEMS Microbiol. Rev. 32, 259–286 (2008).

    CAS  PubMed  Google Scholar 

67. Busse, H. J., Wostmann, C. & Bakker, E. P. The bactericidal action of streptomycin: membrane permeabilization caused by the insertion of mistranslated proteins into the cytoplasmic membrane of Escherichia coli and subsequent caging of the antibiotic inside the cells due to degradation of these proteins. J. Gen. Microbiol. 138, 551–561 (1992).

    CAS  PubMed  Google Scholar 

68. Kohanski, M. A., Dwyer, D. J., Wierzbowski, J., Cottarel, G. & Collins, J. J. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell 135, 679–690 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

69. Akiyama, Y. Quality control of cytoplasmic membrane proteins in Escherichia coli. J. Biochem. 146, 449–454 (2009).

    CAS  PubMed  Google Scholar 

70. Moreno-Cinos, C. et al. ClpP protease, a promising antimicrobial target. Int. J. Mol. Sci. 20, 2232 (2019).

    CAS  PubMed Central  Google Scholar 

71. Brotz-Oesterhelt, H. et al. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat. Med. 11, 1082–1087 (2005).

    PubMed  Google Scholar 

72. Nystrom, T. Not quite dead enough: on bacterial life, culturability, senescence, and death. Arch. Microbiol. 176, 159–164 (2001).

    CAS  PubMed  Google Scholar 

73. Ezraty, B., Gennaris, A., Barras, F. & Collet, J. F. Oxidative stress, protein damage and repair in bacteria. Nat. Rev. Microbiol. 15, 385–396 (2017).

    CAS  PubMed  Google Scholar 

74. Ganesan, A. K. & Smith, K. C. Requirement for protein synthesis in rec-dependent repair of deoxyribonucleic acid in Escherichia coli after ultraviolet or X irradiation. J. Bacteriol. 111, 575–585 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

75. Drlica, K., Malik, M., Kerns, R. J. & Zhao, X. Quinolone-mediated bacterial death. Antimicrob. Agents Chemother. 52, 385–392 (2008).

    CAS  PubMed  Google Scholar 

76. Dwyer, D. J., Kohanski, M. A., Hayete, B. & Collins, J. J. Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol. Syst. Biol. 3, 91 (2007).

    PubMed  PubMed Central  Google Scholar 

77. Singleton, M. R., Dillingham, M. S., Gaudier, M., Kowalczykowski, S. C. & Wigley, D. B. Crystal structure of RecBCD enzyme reveals a machine for processing DNA breaks. Nature 432, 187–193 (2004).

    CAS  PubMed  Google Scholar 

78. Foti, J. J., Devadoss, B., Winkler, J. A., Collins, J. J. & Walker, G. C. Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics. Science 336, 315–319 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

79. Song, L. Y. et al. Exploring synergy between classic mutagens and antibiotics to examine mechanisms of synergy and antibiotic action. Antimicrob. Agents Chemother. 60, 1515–1520 (2015).

    PubMed  Google Scholar 

80. Ocampo, P. S. et al. Antagonism between bacteriostatic and bactericidal antibiotics is prevalent. Antimicrob. Agents Chemother. 58, 4573–4582 (2014).

    PubMed  PubMed Central  Google Scholar 

81. Kouzminova, E. A. & Kuzminov, A. Chromosomal fragmentation in dUTPase-deficient mutants of Escherichia coli and its recombinational repair. Mol. Microbiol. 51, 1279–1295 (2004).

    CAS  PubMed  Google Scholar 

82. Le, L. A. T. et al. Nutritional conditions and oxygen concentration affect spontaneous occurrence of homologous recombination events but not spontaneous mutagenesis in Escherichia coli. Genes Genet. Syst. 95, 85–93 (2020).

    CAS  PubMed  Google Scholar 

83. Bayles, K. W. Bacterial programmed cell death: making sense of a paradox. Nat. Rev. Microbiol. 12, 63–69 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

84. Li, G. W., Burkhardt, D., Gross, C. & Weissman, J. S. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. Cell 157, 624–635 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

85. Quan, S., Skovgaard, O., McLaughlin, R. E., Buurman, E. T. & Squires, C. L. Markerless Escherichia coli rrn deletion strains for genetic determination of ribosomal binding sites. G3 5, 2555–2557 (2015).

    CAS  PubMed  Google Scholar 

86. Imlay, J. A., Chin, S. M. & Linn, S. Toxic D. N. A. damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240, 640–642 (1988).

    CAS  PubMed  Google Scholar 

87. Ezraty, B. et al. Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway. Science 340, 1583–1587 (2013).

    CAS  PubMed  Google Scholar 

88. Liu, Y. & Imlay, J. A. Cell death from antibiotics without the involvement of reactive oxygen species. Science 339, 1210–1213 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

89. Keren, I., Wu, Y., Inocencio, J., Mulcahy, L. R. & Lewis, K. Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science 339, 1213–1216 (2013).

    CAS  PubMed  Google Scholar 

90. Dwyer, D. J. et al. Antibiotics induce redox-related physiological alterations as part of their lethality. Proc. Natl Acad. Sci. USA 111, E2100–E2109 (2014).

    CAS  PubMed  Google Scholar 

91. Dwyer, D. J., Collins, J. J. & Walker, G. C. Unraveling the physiological complexities of antibiotic lethality. Annu. Rev. Pharmacol. Toxicol. 55, 313–332 (2015).

    CAS  PubMed  Google Scholar 

92. Davis, B. D. Mechanism of bactericidal action of aminoglycosides. Microbiol. Rev. 51, 341–350 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

93. Nakamura, Y., Ikeda, M., Nishigaki, R. & Umemura, K. Kinetics of bactericidal activity of aminoglycosides during dynamic dilution. J. Pharmacobiodyn. 8, 695–700 (1985).

    CAS  PubMed  Google Scholar 

94. Nagel, R. & Chan, A. Mistranslation and genetic variability: the effect of streptomycin. Mutat. Res. 601, 162–170 (2006).

    CAS  PubMed  Google Scholar 

95. Ying, L., Zhu, H., Shoji, S. & Fredrick, K. Roles of specific aminoglycoside-ribosome interactions in the inhibition of translation. RNA 25, 247–254 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

96. Gonzalez-Zorn, B. et al. armA and aminoglycoside resistance in Escherichia coli. Emerg. Infect. Dis. 11, 954–956 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

97. Haugan, M. S., Lobner-Olesen, A. & Frimodt-Moller, N. Comparative activity of ceftriaxone, ciprofloxacin, and gentamicin as a function of bacterial growth rate probed by escherichia coli chromosome replication in the mouse peritonitis model. Antimicrob. Agents Chemother. 63, e02133-18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

98. Taber, H. W., Mueller, J. P., Miller, P. F. & Arrow, A. S. Bacterial uptake of aminoglycoside antibiotics. Microbiol. Rev. 51, 439–457 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

99. Ramirez, M. S. & Tolmasky, M. E. Aminoglycoside modifying enzymes. Drug Resist. Updat. 13, 151–171 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

100. Peterson, A. A., Hancock, R. E. & McGroarty, E. J. Binding of polycationic antibiotics and polyamines to lipopolysaccharides of Pseudomonas aeruginosa. J. Bacteriol. 164, 1256–1261 (1985).

     CAS  PubMed  PubMed Central  Google Scholar 

101. Kadurugamuwa, J. L., Clarke, A. J. & Beveridge, T. J. Surface action of gentamicin on Pseudomonas aeruginosa. J. Bacteriol. 175, 5798–5805 (1993).

     CAS  PubMed  PubMed Central  Google Scholar 

102. Dubin, D. T., Hancock, R. & Davis, B. D. The sequence of some effects of streptomycin in Escherichia Coli. Biochim. Biophys. Acta 74, 476–489 (1963).

     CAS  PubMed  Google Scholar 

103. Ji, X. et al. Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity. Proc. Natl Acad. Sci. USA 116, 9578–9585 (2019).

     CAS  PubMed  Google Scholar 

104. Bryan, L. E. & Kwan, S. Roles of ribosomal binding, membrane potential, and electron transport in bacterial uptake of streptomycin and gentamicin. Antimicrob. Agents Chemother. 23, 835–845 (1983).

     CAS  PubMed  PubMed Central  Google Scholar 

105. Hooper, D. C. Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin. Infect. Dis. 32, S9–S15 (2001).

     CAS  PubMed  Google Scholar 

106. Phillips, I., Culebras, E., Moreno, F. & Baquero, F. Induction of the SOS response by new 4-quinolones. J. Antimicrob. Chemother. 20, 631–638 (1987).

     CAS  PubMed  Google Scholar 

107. Mustaev, A. et al. Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding. J. Biol. Chem. 289, 12300–12312 (2014).

     CAS  PubMed  PubMed Central  Google Scholar 

108. Smirnova, G. V. & Oktyabrsky, O. N. Relationship between Escherichia coli growth rate and bacterial susceptibility to ciprofloxacin. FEMS Microbiol. Lett. 365 (2018).

109. Nakamura, Y. & Yura, T. Effects of rifampicin on synthesis and functional activity of DNA-dependent RNA polymerase in Escherichia coli. Mol. Gen. Genet. 145, 227–237 (1976).

     CAS  PubMed  Google Scholar 

110. Gumbo, T. et al. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob. Agents Chemother. 51, 3781–3788 (2007).

     CAS  PubMed  PubMed Central  Google Scholar 

111. Zhang, Z. et al. Could high-concentration rifampicin kill rifampicin-resistant M. tuberculosis? Rifampicin MIC test in rifampicin-resistant isolates from patients with osteoarticular tuberculosis. J. Orthop. Surg. Res. 9, 124 (2014).

     PubMed  PubMed Central  Google Scholar 

112. Burmann, B. M. et al. A NusE:NusG complex links transcription and translation. Science 328, 501–504 (2010).

     CAS  PubMed  Google Scholar 

113. Proshkin, S., Rahmouni, A. R., Mironov, A. & Nudler, E. Cooperation between translating ribosomes and RNA polymerase in transcription elongation. Science 328, 504–508 (2010).

     CAS  PubMed  PubMed Central  Google Scholar 

114. Amitai, S., Yassin, Y. & Engelberg-Kulka, H. MazF-mediated cell death in Escherichia coli: a point of no return. J. Bacteriol. 186, 8295–8300 (2004).

     CAS  PubMed  PubMed Central  Google Scholar 

115. Amitai, S., Kolodkin-Gal, I., Hananya-Meltabashi, M., Sacher, A. & Engelberg-Kulka, H. Escherichia coli MazF leads to the simultaneous selective synthesis of both “death proteins” and “survival proteins”. PLoS Genet. 5, e1000390 (2009).

     PubMed  PubMed Central  Google Scholar 

116. Saito, K. et al. Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc. Natl Acad. Sci. USA 114, E4832–E4840 (2017).

     CAS  PubMed  Google Scholar 

117. Kannan, K., Vazquez-Laslop, N. & Mankin, A. S. Selective protein synthesis by ribosomes with a drug-obstructed exit tunnel. Cell 151, 508–520 (2012).

     CAS  PubMed  Google Scholar 

118. Mosaei, H. & Zenkin, N. Inhibition of RNA polymerase by rifampicin and rifamycin-like molecules. EcoSal Plus https://doi.org/10.1128/ecosalplus.ESP-0017-2019 (2020).

     Article  PubMed  Google Scholar 

119. Tipper, D. J. & Strominger, J. L. Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine. Proc. Natl Acad. Sci. USA 54, 1133–1141 (1965).

     CAS  PubMed  Google Scholar 

120. Chung, H. S. et al. Rapid beta-lactam-induced lysis requires successful assembly of the cell division machinery. Proc. Natl Acad. Sci. USA 106, 21872–21877 (2009).

     CAS  PubMed  Google Scholar 

121. Lee, A. J. et al. Robust, linear correlations between growth rates and beta-lactam-mediated lysis rates. Proc. Natl Acad. Sci. USA 115, 4069–4074 (2018).

     CAS  PubMed  Google Scholar 

122. Tomasz, A. The mechanism of the irreversible antimicrobial effects of penicillins: how the beta-lactam antibiotics kill and lyse bacteria. Annu. Rev. Microbiol. 33, 113–137 (1979).

     CAS  PubMed  Google Scholar 

123. Cho, H., Uehara, T. & Bernhardt, T. G. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell 159, 1300–1311 (2014).

     CAS  PubMed  PubMed Central  Google Scholar 

124. Mercier, R., Kawai, Y. & Errington, J. Excess membrane synthesis drives a primitive mode of cell proliferation. Cell 152, 997–1007 (2013).

     CAS  PubMed  Google Scholar 

125. Koonin, E. V. & Mulkidjanian, A. Y. Evolution of cell division: from shear mechanics to complex molecular machineries. Cell 152, 942–944 (2013).

     CAS  PubMed  Google Scholar 

126. Booth, S. & Lewis, R. J. Structural basis for the coordination of cell division with the synthesis of the bacterial cell envelope. Protein Sci. 28, 2042–2054 (2019).

     CAS  PubMed  PubMed Central  Google Scholar 

127. Minato, Y. et al. Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole. Nat. Commun. 9, 1003 (2018).

     PubMed  PubMed Central  Google Scholar 

128. Van Bambeke, F., Van Laethem, Y., Courvalin, P. & Tulkens, P. M. Glycopeptide antibiotics: from conventional molecules to new derivatives. Drugs 64, 913–936 (2004).

     PubMed  Google Scholar 

129. Joukhadar, C., Pillai, S., Wennersten, C., Moellering, R. C. Jr. & Eliopoulos, G. M. Lack of bactericidal antagonism or synergism in vitro between oxacillin and vancomycin against methicillin-susceptible strains of Staphylococcus aureus. Antimicrob. Agents Chemother. 54, 773–777 (2010).

     CAS  PubMed  Google Scholar 

130. Cui, L. et al. Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. Antimicrob. Agents Chemother. 50, 428–438 (2006).

     CAS  PubMed  PubMed Central  Google Scholar 

131. Larsson, A. J., Walker, K. J., Raddatz, J. K. & Rotschafer, J. C. The concentration-independent effect of monoexponential and biexponential decay in vancomycin concentrations on the killing of Staphylococcus aureus under aerobic and anaerobic conditions. J. Antimicrob. Chemother. 38, 589–597 (1996).

     CAS  PubMed  Google Scholar 

132. Ladjouzi, R. et al. Analysis of the tolerance of pathogenic enterococci and Staphylococcus aureus to cell wall active antibiotics. J. Antimicrob. Chemother. 68, 2083–2091 (2013).

     CAS  PubMed  Google Scholar 

133. Amyes, S. G. Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12. Antimicrob. Agents Chemother. 21, 288–293 (1982).

     CAS  PubMed  PubMed Central  Google Scholar 

134. Then, R. & Angehrn, P. Nature of the bacterial action of sulfonamides and trimethoprim, alone and in combination. J. Infect. Dis. 128, 498–501 (1973).

     Google Scholar 

135. Ahmad, S. I., Kirk, S. H. & Eisenstark, A. Thymine metabolism and thymineless death in prokaryotes and eukaryotes. Annu. Rev. Microbiol. 52, 591–625 (1998).

     CAS  PubMed  Google Scholar 

136. Khan, S. R. & Kuzminov, A. Thymineless death in Escherichia coli is unaffected by chromosomal replication complexity. J. Bacteriol. 201, e00797-18 (2019).

     Google Scholar 

137. Cambau, E. et al. Jacques F. Acar (1931–2020). Clin. Microbiol. Infect. 26, 1261–1263 (2020).

     CAS  PubMed  PubMed Central  Google Scholar 

Page 2

The findings of time–kill experiments measured as changes in the viable cell density of Staphylococcus aureus Newman exposed to 10 times the minimum inhibitory concentration of nine different antibiotics in Mueller–Hinton II medium at 37 °C with aeration are shown. Bacteriostatic antibiotics (left) stop growth and colony-forming units (CFUs) remain stable. By contrast, bactericidal antibiotics (right) kill bacteria and thus the CFUs drop. Of note, a resistant mutant emerged in the culture treated with rifampin, leading to resumed growth at the end of the experiment.