Journal Article

The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II)

Hesketh, Andrew R., Hong, Hee-Jeon, Zarkan, Ashraf, Macklyne, Heather-Rose, Truman, Andrew W.

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/90 / 42 / 631/326/22/1290 / 631/45/56 / 82/16 / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria - drug effects / Bacteria - metabolism / Bacterial physiology / Bacterial Proteins - metabolism / Binding sites / Deuterium Oxide - chemistry / Drug resistance / Fluorometry / Homeostasis / Homeostasis - drug effects / Humanities and Social Sciences / Methicillin / Microbial Sensitivity Tests / multidisciplinary / NMR / Nosocomial infection / Nuclear magnetic resonance / Proton Magnetic Resonance Spectroscopy / Science / Solutions / Staphylococcus infections / Vancomycin / Vancomycin - pharmacology / Zinc / Zinc - metabolism