Antibiotic efficacy is linked to bacterial cellular respiration

By M. Lobritz, Peter Belenky, C. Porter, Arnaud Gutierrez, Jason H. Yang, Eric G. Schwarz, Daniel J. Dwyer, Ahmad S. Khalil, James J. Collins. Proceedings of the National Academy of Sciences of the United States of America, 2015

699 citations recorded by the source corpus.

Significance The global burden of antibiotic resistance has created a demand to better understand the basic mechanisms of existing antibiotics. Of significant interest is how antibiotics may perturb bacterial metabolism, and how bacterial metabolism may influence antibiotic activity. Here, we study the interaction of bacteriostatic and bactericidal antibiotics, the two major phenotypic drug classes. Interestingly, the two classes differentially perturb bacterial cellular respiration, with major consequences for their intrinsic activity both alone and in combination. Of note, bacteriostatic antibiotics decelerate cellular respiration, generating a metabolic state that is prohibitive to killing. Further, we show that the efficacy of bactericidal drugs can be improved by increasing basal respiration, and we identify a respiration-related drug target that potentiates the activity of bactericidal antibiotics. 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.

Subfields: Infectious Diseases, Molecular Biology, Molecular Medicine

View Paper: https://www.semanticscholar.org/paper/42100aded8314f529679ab0d62badc491ae90492

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In Infectious Diseases

James J. Collins

In Molecular Biology

In Molecular Medicine

Citations in the corpus

A white-box machine learning approach for revealing antibiotic mechanisms of action (2019, positive): “These findings are consistent with previous observations that protein translation inhibitors generally exert antagonistic effects on antibiotic lethality (Lobritz et al., 2015; Ocampo et al., 2014).”
A Deep Learning Approach to Antibiotic Discovery. (2020, background): “The efﬁcacy of halicin against antibiotic-tolerant cells represents a signiﬁcant improvement over the majority of conventional antibiotics (Lobritz et al., 2015; Stokes et al., 2019b).”