Proximate and Ultimate Causes of the Bactericidal Action of Antibiotics

Overview

Journal Nat Rev Microbiol

Specialties Infectious Diseases
Microbiology

Date 2020 Oct 7

PMID 33024310

Citations 74

Authors

Fernando Baquero

Bruce R Levin

Affiliations

Soon will be listed here.

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.

Citing Articles

Enhancing antibiotic therapy through comprehensive pharmacokinetic/pharmacodynamic principles.

Alikhani M, Nazari M, Hatamkhani S Front Cell Infect Microbiol. 2025; 15:1521091.

PMID: 40070375 PMC: 11893874. DOI: 10.3389/fcimb.2025.1521091.

Advancing antibiotic discovery with bacterial cytological profiling: a high-throughput solution to antimicrobial resistance.

Salgado J, Rayner J, Ojkic N Front Microbiol. 2025; 16:1536131.

PMID: 40018674 PMC: 11865948. DOI: 10.3389/fmicb.2025.1536131.

Effects of Comparative Killing by Pradofloxacin and Seven Other Antimicrobials Against Varying Bacterial Densities of Swine Isolates of .

Blondeau J, Fitch S Microorganisms. 2025; 13(2).

PMID: 40005588 PMC: 11857592. DOI: 10.3390/microorganisms13020221.

The role of bacterial metabolism in antimicrobial resistance.

Ahmad M, Aduru S, Smith R, Zhao Z, Lopatkin A Nat Rev Microbiol. 2025; .

PMID: 39979446 DOI: 10.1038/s41579-025-01155-0.

Ex vivo oral biofilm model for rapid screening of antimicrobial agents including natural cranberry polyphenols.

Adami G, Li W, Green S, Kim E, Wu C Sci Rep. 2025; 15(1):6130.

PMID: 39971954 PMC: 11840115. DOI: 10.1038/s41598-025-87382-0.

References

Song L, DSouza S, Lam K, Kang T, Yeh P, Miller J . Exploring Synergy between Classic Mutagens and Antibiotics To Examine Mechanisms of Synergy and Antibiotic Action. Antimicrob Agents Chemother. 2015; 60(3):1515-20. PMC: 4775987. DOI: 10.1128/AAC.02485-15. View

Mainardi J, Legrand R, Arthur M, Schoot B, van Heijenoort J, Gutmann L . Novel mechanism of beta-lactam resistance due to bypass of DD-transpeptidation in Enterococcus faecium. J Biol Chem. 2000; 275(22):16490-6. DOI: 10.1074/jbc.M909877199. View

Udekwu K, Levin B . Staphylococcus aureus in continuous culture: a tool for the rational design of antibiotic treatment protocols. PLoS One. 2012; 7(7):e38866. PMC: 3401188. DOI: 10.1371/journal.pone.0038866. View

Hooper D . Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis. 2001; 32 Suppl 1:S9-S15. DOI: 10.1086/319370. View

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. 2014; 116(6):1427-37. DOI: 10.1111/jam.12474. View

Amitai S, Yassin Y, Engelberg-Kulka H . MazF-mediated cell death in Escherichia coli: a point of no return. J Bacteriol. 2004; 186(24):8295-300. PMC: 532418. DOI: 10.1128/JB.186.24.8295-8300.2004. View

Kohanski M, Dwyer D, Hayete B, Lawrence C, Collins J . A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007; 130(5):797-810. DOI: 10.1016/j.cell.2007.06.049. View

Cui L, Iwamoto A, Lian J, Neoh H, Maruyama T, Horikawa Y . Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2006; 50(2):428-38. PMC: 1366884. DOI: 10.1128/AAC.50.2.428-438.2006. View

Pages J, James C, Winterhalter M . The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol. 2008; 6(12):893-903. DOI: 10.1038/nrmicro1994. View

10.

Larsson A, Walker K, Raddatz J, Rotschafer J . 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. 1996; 38(4):589-97. DOI: 10.1093/jac/38.4.589. View

11.

Kannan K, Vazquez-Laslop N, Mankin A . Selective protein synthesis by ribosomes with a drug-obstructed exit tunnel. Cell. 2012; 151(3):508-20. DOI: 10.1016/j.cell.2012.09.018. View

12.

Linares J, Gustafsson I, Baquero F, Martinez J . Antibiotics as intermicrobial signaling agents instead of weapons. Proc Natl Acad Sci U S A. 2006; 103(51):19484-9. PMC: 1682013. DOI: 10.1073/pnas.0608949103. View

13.

Eliopoulos G, Eliopoulos C . Antibiotic combinations: should they be tested?. Clin Microbiol Rev. 1988; 1(2):139-56. PMC: 358039. DOI: 10.1128/CMR.1.2.139. View

14.

Moreno-Cinos C, Goossens K, Salado I, Van der Veken P, De Winter H, Augustyns K . ClpP Protease, a Promising Antimicrobial Target. Int J Mol Sci. 2019; 20(9). PMC: 6540193. DOI: 10.3390/ijms20092232. View

15.

Liu Y, Imlay J . Cell death from antibiotics without the involvement of reactive oxygen species. Science. 2013; 339(6124):1210-3. PMC: 3731989. DOI: 10.1126/science.1232751. View

16.

Calabrese E . Hormesis: a fundamental concept in biology. Microb Cell. 2017; 1(5):145-149. PMC: 5354598. DOI: 10.15698/mic2014.05.145. View

17.

Chung H, Yao Z, Goehring N, Kishony R, Beckwith J, Kahne D . Rapid beta-lactam-induced lysis requires successful assembly of the cell division machinery. Proc Natl Acad Sci U S A. 2009; 106(51):21872-7. PMC: 2799840. DOI: 10.1073/pnas.0911674106. View

18.

Yao Z, Kahne D, Kishony R . Distinct single-cell morphological dynamics under beta-lactam antibiotics. Mol Cell. 2012; 48(5):705-12. PMC: 3525771. DOI: 10.1016/j.molcel.2012.09.016. View

19.

Van Bambeke F, Van Laethem Y, Courvalin P, Tulkens P . Glycopeptide antibiotics: from conventional molecules to new derivatives. Drugs. 2004; 64(9):913-36. DOI: 10.2165/00003495-200464090-00001. View

20.

Silhavy T, Kahne D, Walker S . The bacterial cell envelope. Cold Spring Harb Perspect Biol. 2010; 2(5):a000414. PMC: 2857177. DOI: 10.1101/cshperspect.a000414. View