A role for the bacterial GATC methylome in antibiotic stress survival
Author(s)
Ross, Christian A; Belenky, Peter; Li, Hu; Cohen, Nadia; Jain, Saloni R.; Gutierrez, Arnaud; Collins, James J.; Shapiro, Rebecca; ... Show more Show less
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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.
Date issued
2016-06Department
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 EngineeringJournal
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
ISSN
1061-4036
1546-1718