Format

Send to

Choose Destination
Nat Genet. 2016 May;48(5):581-6. doi: 10.1038/ng.3530. Epub 2016 Mar 21.

A role for the bacterial GATC methylome in antibiotic stress survival.

Cohen NR1,2,3, Ross CA4, Jain S2,5, Shapiro RS2,6, Gutierrez A2,6, Belenky P7, Li H4, Collins JJ1,2,3,5,6,8,9.

Author information

1
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
2
Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
4
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Information Technology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
5
Boston University, Boston, Massachusetts, USA.
6
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
7
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA.
8
Harvard-MIT Program in Health Sciences and Technology, Boston, Massachusetts, USA.
9
Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

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.

PMID:
26998690
PMCID:
PMC4848143
DOI:
10.1038/ng.3530
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center