Growth rate and metabolic state of bacteria have been separately shown to affect antibiotic efficacy1,2,3. However, the two are interrelated as bacterial growth inherently imposes a metabolic burden4; thus, determining individual contributions from each is challenging5,6. Indeed, faster growth is often correlated with increased antibiotic efficacy7,8; however, the concurrent role of metabolism in that relationship has not been well characterized. As a result, a clear understanding of the interdependence between growth and metabolism, and their implications for antibiotic efficacy, are lacking9. Here, we measured growth and metabolism in parallel across a broad range of coupled and uncoupled conditions to determine their relative contribution to antibiotic lethality. We show that when growth and metabolism are uncoupled, antibiotic lethality uniformly depends on the bacterial metabolic state at the time of treatment, rather than growth rate. We further reveal a critical metabolic threshold below which antibiotic lethality is negligible. These findings were general for a wide range of conditions, including nine representative bactericidal drugs and a diverse range of Gram-positive and Gram-negative species (Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus). This study provides a cohesive metabolic-dependent basis for antibiotic-mediated cell death, with implications for current treatment strategies and future drug development.
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The data that support the findings of this study are available from the corresponding author on reasonable request.
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We thank D. Hung from the Broad Institute for providing the bacterial pathogens used in this study; J. K. Srimani, R. P. Smith and S. Bening for input on data interpretation and manuscript editing. This work was supported by the Defence Threat Reduction Agency (grant number HDTRA1-15-1-0051), the National Institutes of Health (grant number K99GM118907), the Banting Postdoctoral Fellowship Program (to J.M.S.; grant number 393360), the Broad Institute of MIT and Harvard, and a generous gift from A. Bekenstein and J. Bekenstein.
J.J.C. is scientific co-founder and Scientific Advisory Board chair of EnBiotix, an antibiotic drug discovery company.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Lopatkin, A.J., Stokes, J.M., Zheng, E.J. et al. Bacterial metabolic state more accurately predicts antibiotic lethality than growth rate. Nat Microbiol 4, 2109–2117 (2019). https://doi.org/10.1038/s41564-019-0536-0
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