Bacterial metabolic state more accurately predicts antibiotic lethality than growth rate
Name
nihms-1054958.pdf
Description
Accepted version
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1.05 MB
Format
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Checksum (MD5)
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Author(s)
Lopatkin, Allison J
Stokes, Jonathan M
Zheng, Erica J
Yang, Jason H
Takahashi, Melissa K
You, Lingchong
Collins, James J
Date Issued
2019
Journal
Nature Microbiology
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Growth rate and metabolic state of bacteria have been separately shown to affect antibiotic efficacy1–3. 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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Synthetic Biology Center
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1038/S41564-019-0536-0
