A role for the bacterial GATC methylome in antibiotic stress survival

• Main Authors: Ross, Christian A (Author), Belenky, Peter (Author), Li, Hu (Author), Cohen, Nadia (Contributor), Jain, Saloni R. (Contributor), Gutierrez, Arnaud (Contributor), Collins, James J. (Contributor), Shapiro, Rebecca (Author)
• Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Harvard University- (Contributor), Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Shapiro, Rebecca Sara (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2017-01-27T22:00:13Z.
• Subjects: Article
• Online Access: Get fulltext

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.
United States. Defense Threat Reduction Agency (Grant HDTRA1-15-1-0051)
National Institutes of Health (U.S.) (Grant 1U54GM114838-01)
Howard Hughes Medical Institute
Canadian Institutes of Health Research (Banting Postdoctoral Fellowship)
Wyss Institute for Biologically Inspired Engineering
Mayo Clinic Center for Individualized Medicine
Donors Cure Foundation