A role for the bacterial GATC methylome in antibiotic stress survival

Nadia R. Cohen, Christian A. Ross, Saloni Jain, Rebecca S. Shapiro, Arnaud Gutierrez, Peter Belenky, Hu Li, James J. Collins

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Antibiotic resistance is an increasingly serious public health threat. 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.

Original languageEnglish (US)
Pages (from-to)581-586
Number of pages6
JournalNature Genetics
Volume48
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Genetics

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