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Inhibition of the Broad Spectrum Nonmetallocarbapenamase of Class A (NMC-A) ␤-Lactamase from Enterobacter cloacae by Monocyclic ␤-Lactams* □ S

Abstract : ␤-Lactamases hydrolyze ␤-lactam antibiotics, a reaction that destroys their antibacterial activity. These enzymes , of which four classes are known, are the primary cause of resistance to ␤-lactam antibiotics. The class A ␤-lactamases form the largest group. A novel class A ␤-lactamase, named the nonmetallocarbapenamase of class A (NMC-A) ␤-lactamase, has been discovered recently that has a broad substrate profile that included carbapenem antibiotics. This is a serious development, since carbapenems have been relatively immune to the action of these resistance enzymes. Inhibitors for this enzyme are sought. We describe herein that a type of monobactam molecule of our design inactivates the NMC-A ␤-lactamase rapidly, efficiently, and irreversibly. The mechanism of inactivation was investigated by solving the x-ray structure of the inhibited NMC-A enzyme to 1.95 Å resolution. The structure shed light on the nature of the fragmentation of the inhibitor on enzyme acylation and indicated that there are two acyl-enzyme species that account for enzyme inhibition. Each of these inhibited enzyme species is trapped in a distinct local energy minimum that does not predispose the inhibitor species for deacylation, accounting for the irreversible mode of enzyme inhibition. Molecular dynamics simulations provided evidence in favor of a dynamic motion for the acyl-enzyme species, which samples a considerable conformational space prior to the entrapment of the two stable acyl-enzyme species in the local energy minima. A discussion of the likelihood of such dynamic motion for turnover of substrates during the normal catalytic processes of the enzyme is presented.
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Lionel Mourey, Lakshmi Kotra, John Bellettiniʈ, Alexey Bulychev, Michael O'Brien, et al.. Inhibition of the Broad Spectrum Nonmetallocarbapenamase of Class A (NMC-A) ␤-Lactamase from Enterobacter cloacae by Monocyclic ␤-Lactams* □ S. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 1999, 274, pp.25260 - 25265. ⟨hal-03004384⟩

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