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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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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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