title: A role for the bacterial GATC methylome in antibiotic stress survival.
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.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.|Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Nadia R
authors.initials: NR
authors.lastname: Cohen
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Information Technology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Boston University, Boston, Massachusetts, USA.
authors.forename: Saloni
authors.initials: S
authors.lastname: Jain
authors.affiliation: Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shapiro
authors.affiliation: Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Belenky
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Information Technology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.|Institute for Medical Engineering and Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.|Boston University, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Harvard-MIT Program in Health Sciences and Technology, Boston, Massachusetts, USA.|Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
mesh_terms: D000225:Adenine / Q000378:metabolism; D019175:DNA Methylation; D004269:DNA, Bacterial / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological
chemical_list: D004269:DNA, Bacterial; D000225:Adenine