05/01/2013
Defeating NDM-1
There are serious concerns about increased antibiotic resistance in pathogens.
The Science
The New Delhi metallo-beta-lactamase (NDM-1) represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known β-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 researchers report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. Researchers 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 β-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the β-lactam ring through a proton shuttle.
Summary
The NDM-1 gene makes multiple pathogenic microorganisms resistant to all known beta-lactam antibiotics including carbapenems, which are considered as “last resort” antibiotics. Researchers used the Advanced Photon Source at Argonne National Laboratory to determine the structural basis for NDM-1’s promiscuous activity via a combination of crystallographic and biochemical studies and theoretical calculations that elucidated a pH-dependent set of pathways. Based on these findings, future active drugs can be predicted.
BER Program Manager
Dawn Adin
U.S. Department of Energy, Biological and Environmental Research (SC-33)
Biological Systems Science Division
[email protected]
References
Kim, Y., M. A. Cunningham, J. Mire, C. Tesar, J. Sacchettini, and A. Joachimiak. 2013. “NDM-1, the Ultimate Promiscuous Enzyme: Substrate Recognition and Catalytic Mechanism,” The FASEB Journal 27(5). DOI:10.1096/fj.12-224014.