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Nat Microbiol DOI:10.1038/s41564-019-0536-0

Bacterial metabolic state more accurately predicts antibiotic lethality than growth rate.

Publication TypeJournal Article
Year of Publication2019
AuthorsLopatkin, AJ, Stokes, JM, Zheng, EJ, Yang, JH, Takahashi, MK, You, L, Collins, JJ
JournalNat Microbiol
Date Published2019 Aug 26
ISSN2058-5276
Abstract

Growth rate and metabolic state of bacteria have been separately shown to affect antibiotic efficacy. However, the two are interrelated as bacterial growth inherently imposes a metabolic burden; thus, determining individual contributions from each is challenging. Indeed, faster growth is often correlated with increased antibiotic efficacy; 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 lacking. 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.

DOI10.1038/s41564-019-0536-0
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31451773?dopt=Abstract

Alternate JournalNat Microbiol
PubMed ID31451773
Grant ListHDTRA1-15-1-0051 / / United States Department of Defense | Defense Threat Reduction Agency (DTRA) /
393360 / / Banting Research Foundation (BRF) /
K99GM118907 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /