Journal
FASEB JOURNAL
Volume 27, Issue 5, Pages 1917-1927Publisher
WILEY
DOI: 10.1096/fj.12-224014
Keywords
metallo-beta-lactamase; antibiotic resistance; pH dependence
Categories
Funding
- U.S. National Institutes of Health [GM094585, GM094568]
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- National Science Foundation's FaST program [HRD-0703584]
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The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a new enzyme, first identified in Klebsiella pneumoniae from a patient from New Delhi and denoted as NDM-1, represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known beta-lactam-based antibiotics with startling efficiency. NDM-1 can utilize different metal cofactors and seems to exploit an alternative mechanism based on the reaction conditions. Here we report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. We utilize structures obtained through X-ray crystallography, biochemical assays, and numerical simulation to construct a model of the enzyme catalytic pathway. The NDM-1 enzyme interacts with the substrate solely through zinc, or other metals, bound in the active site, explaining the observed lack of specificity against a broad range of beta-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the beta-lactam ring through a proton shuttle.-Kim, Y., Cunningham, M. A.; Mire, J., Tesar, C., Sacchettini, J., Joachimiak, A. NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism. FASEB J. 27, 1917-1927 (2013). www.fasebj.org
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