Reactive metabolic byproducts contribute to antibiotic lethality under anaerobic conditions

Mol Cell. 2022 Sep 15;82(18):3499-3512.e10. doi: 10.1016/j.molcel.2022.07.009. Epub 2022 Aug 15.

Abstract

Understanding how bactericidal antibiotics kill bacteria remains an open question. Previous work has proposed that primary drug-target corruption leads to increased energetic demands, resulting in the generation of reactive metabolic byproducts (RMBs), particularly reactive oxygen species, that contribute to antibiotic-induced cell death. Studies have challenged this hypothesis by pointing to antibiotic lethality under anaerobic conditions. Here, we show that treatment of Escherichia coli with bactericidal antibiotics under anaerobic conditions leads to changes in the intracellular concentrations of central carbon metabolites, as well as the production of RMBs, particularly reactive electrophilic species (RES). We show that antibiotic treatment results in DNA double-strand breaks and membrane damage and demonstrate that antibiotic lethality under anaerobic conditions can be decreased by RMB scavengers, which reduce RES accumulation and mitigate associated macromolecular damage. This work indicates that RMBs, generated in response to antibiotic-induced energetic demands, contribute in part to antibiotic lethality under anaerobic conditions.

Keywords: anaerobic; antibiotic resistance; antibiotics; antioxidants; macromolecular damage; mass spectrometry; mechanism of action; metabolism; reactive electrophilic species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anaerobiosis
  • Anti-Bacterial Agents* / metabolism
  • Anti-Bacterial Agents* / pharmacology
  • Carbon / metabolism
  • DNA / metabolism
  • Escherichia coli* / genetics
  • Escherichia coli* / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Anti-Bacterial Agents
  • Reactive Oxygen Species
  • Carbon
  • DNA