title: The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II).
abstract: Vancomycin is a front-line antibiotic used for the treatment of nosocomial infections, particularly those caused by methicillin-resistant Staphylococcus aureus. Despite its clinical importance the global effects of vancomycin exposure on bacterial physiology are poorly understood. In a previous transcriptomic analysis we identified a number of Zur regulon genes which were highly but transiently up-regulated by vancomycin in Streptomyces coelicolor. Here, we show that vancomycin also induces similar zinc homeostasis systems in a range of other bacteria and demonstrate that vancomycin binds to Zn(II) in vitro. This implies that vancomycin treatment sequesters zinc from bacterial cells thereby triggering a Zur-dependent zinc starvation response. The Kd value of the binding between vancomycin and Zn(II) was calculated using a novel fluorometric assay, and NMR was used to identify the binding site. These findings highlight a new biologically relevant aspect of the chemical property of vancomycin as a zinc chelator.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, UK.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Zarkan
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, UK.
authors.forename: Heather-Rose
authors.initials: HR
authors.lastname: Macklyne
authors.affiliation: Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Truman
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, UK.|Cambridge Systems Biology Centre, University of Cambridge, Cambridge, CB2 1QW, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hesketh
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, UK.
authors.forename: Hee-Jeon
authors.initials: HJ
authors.lastname: Hong
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D017666:Deuterium Oxide / Q000737:chemistry; D005470:Fluorometry; D006706:Homeostasis / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D066244:Proton Magnetic Resonance Spectroscopy; D012996:Solutions; D014640:Vancomycin / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012996:Solutions; D014640:Vancomycin; D015032:Zinc; D017666:Deuterium Oxide