HAL will be down for maintenance from Friday, June 10 at 4pm through Monday, June 13 at 9am. More information
Skip to Main content Skip to Navigation
Journal articles

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.
Document type :
Journal articles
Complete list of metadata

Cited literature [25 references]  Display  Hide  Download

Contributor : Lionel Mourey Connect in order to contact the contributor
Submitted on : Friday, November 20, 2020 - 3:59:42 PM
Last modification on : Thursday, November 25, 2021 - 5:22:04 PM


Publisher files allowed on an open archive


  • HAL Id : hal-03004384, version 1



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⟩



Record views


Files downloads