Antibiotic efficacy is linked to bacterial cellular respiration

TLDR

Bacteriostatic antibiotics inhibit bacterial growth while bactericidal antibiotics cause cell death, and both target energy‑consuming processes, implying that antibiotic treatment may alter bacterial metabolism. The authors hypothesized that the distinct metabolic effects of bacteriostatic and bactericidal antibiotics determine their overall efficacy. By combining bacteriostatic and bactericidal drugs and performing global metabolic profiling, the study revealed that drug‑target metabolites accumulate and feed the electron transport chain. The findings showed that bacteriostatic antibiotics suppress cellular respiration, bactericidal antibiotics accelerate it, and that modulating respiration—through cytochrome oxidase inhibition or ATP‑synthesis uncoupling—can respectively reduce or enhance bactericidal killing, linking respiration to antibiotic efficacy.

Abstract

Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.