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  • Perspective
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Proximate and ultimate causes of the bactericidal action of antibiotics

Nature Reviews Microbiology volume 19, pages 123–132 (2021)Cite this article

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Abstract

During the past 85 years of antibiotic use, we have learned a great deal about how these ‘miracle’ drugs work. We know the molecular structures and interactions of these drugs and their targets and the effects on the structure, physiology and replication of bacteria. Collectively, we know a great deal about these proximate mechanisms of action for virtually all antibiotics in current use. What we do not know is the ultimate mechanism of action; that is, how these drugs irreversibly terminate the ‘individuality’ of bacterial cells by removing barriers to the external world (cell envelopes) or by destroying their genetic identity (DNA). Antibiotics have many different ‘mechanisms of action’ that converge to irreversible lethal effects. In this Perspective, we consider what our knowledge of the proximate mechanisms of action of antibiotics and the pharmacodynamics of their interaction with bacteria tell us about the ultimate mechanisms by which these antibiotics kill bacteria.

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Fig. 1: Killing rates of different antibiotics.
Fig. 2: Factors influencing the bactericidal activity of antibiotics in a susceptible bacterial cell.
Fig. 3: Successive steps in the process of bacterial killing by antibiotics from six families.

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References

  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 

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Acknowledgements

The authors are grateful to their awesome wives, Ros and Adriana, for putting up with them during this period of COVID-19 quarantine and supporting their playing fun games such as reviewing the literature and writing this Perspective. They thank I. McCall for a careful reading of this manuscript, and J. Rodríguez-Beltrán for discussion about some critical concepts. This research was funded by grants from the U.S. National Institutes of General Medical Science (GM091875-17 and 1R35 GM136407-01) to B.R.L and from the Regional Government of Madrid (InGeMICS- B2017/BMD-3691) and the Ramón Areces Foundation to the F.B. laboratory. The authors dedicate this Perspective to the memory of J. Acar137, with whom they would have loved to have discussed the question of how antibiotics kill; from those conversations with Jacques, the authors know they would have had much more to tell you about the answer.

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  1. Department of Microbiology, Ramón y Cajal Institute for Health Research (IRYCIS), Ramón y Cajal University Hospital, Madrid, Spain

    Fernando Baquero

  2. Department of Biology, Emory University, Atlanta, GA, USA

    Bruce R. Levin

  3. Antibiotic Resistance Center, Emory University, Atlanta, GA, USA

    Bruce R. Levin

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  1. Fernando Baquero
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Baquero, F., Levin, B.R. Proximate and ultimate causes of the bactericidal action of antibiotics. Nat Rev Microbiol 19, 123–132 (2021). https://doi.org/10.1038/s41579-020-00443-1

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