A role for the bacterial GATC methylome in antibiotic stress survival
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Author(s)
Ross, Christian A
Belenky, Peter
Li, Hu
Cohen, Nadia
Jain, Saloni R.
Gutierrez, Arnaud
Collins, James J.
Shapiro, Rebecca
Date Issued
June 2016
Journal
Nature Genetics
Publisher
Nature Publishing Group
Citation
Cohen, Nadia R et al. “A Role for the Bacterial GATC Methylome in Antibiotic Stress Survival.” Nature Genetics 48.5 (2016): 581–586.
Version
Author's final manuscript
Abstract
Antibiotic resistance is an increasingly serious public health threat1. Understanding pathways allowing bacteria to survive antibiotic stress may unveil new therapeutic targets. We explore the role of the bacterial epigenome in antibiotic stress survival using classical genetic tools and single-molecule real-time sequencing to characterize genomic methylation kinetics. We find that Escherichia coli survival under antibiotic pressure is severely compromised without adenine methylation at GATC sites. Although the adenine methylome remains stable during drug stress, without GATC methylation, methyl-dependent mismatch repair (MMR) is deleterious and, fueled by the drug-induced error-prone polymerase Pol IV, overwhelms cells with toxic DNA breaks. In multiple E. coli strains, including pathogenic and drug-resistant clinical isolates, DNA adenine methyltransferase deficiency potentiates antibiotics from the β-lactam and quinolone classes. This work indicates that the GATC methylome provides structural support for bacterial survival during antibiotic stress and suggests targeting bacterial DNA methylation as a viable approach to enhancing antibiotic activity.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/ng.3530
