title: Glycopeptide sulfation evades resistance.
abstract: The incidence of antibiotic resistance among pathogenic microorganisms is increasing at an alarming rate. Resistance against front-line therapeutics such as the glycopeptide antibiotic vancomycin has emerged and has spread to highly virulent pathogens, including Staphylococcus aureus. Glycopeptide antibiotics are natural products from the Actinomycetes that have a characteristic heptapeptide core. The chemical diversity of the class is achieved through glycosylation, halogenation, methylation, and acylation of the core, modifications that are implicated in improved solubility, stability, or activity of the molecule. Sulfation is yet another modification observed infrequently in glycopeptides, but its role is not known. Although glycopeptide sulfotransferases are found in the environmental metagenome and must therefore serve an evolutionary purpose, all previous studies have reported decreased antibiotic activity with sulfation. We report that sulfation of glycopeptides has little effect on the compound's ability to bind its target, the d-Ala-d-Ala peptidoglycan precursors of the bacterial cell wall. However, sulfation does impact glycopeptide dimerization, and importantly, sulfated glycopeptides are significantly less potent inducers of the resistance gene cluster vanHAX in actinomycetes. Our results begin to unravel the mystery of the biological role of glycopeptide sulfation and offer a potential new strategy for the development of new antibiotics that avoid resistance.
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kalan
authors.forename: Julie
authors.initials: J
authors.lastname: Perry
authors.forename: Kalinka
authors.initials: K
authors.lastname: Koteva
authors.forename: Maulik
authors.initials: M
authors.lastname: Thaker
authors.forename: Gerard
authors.initials: G
authors.lastname: Wright
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002151:Calorimetry / Q000379:methods; D019729:Carbon-Oxygen Ligases / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006020:Glycopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013302:Streptomyces / Q000187:drug effects*; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006020:Glycopeptides; C071437:VanA ligase, Bacteria; D019729:Carbon-Oxygen Ligases