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Publication Abstract from PubMed

Carbapenem antibiotics are used as a last-resort treatment for infections caused by multidrug-resistant bacteria. The wide spread of carbapenemases in Gram-negative bacteria has severely compromised the utility of these drugs and represents a serious public health threat. To combat carbapenemase-mediated resistance, new antimicrobials and inhibitors of these enzymes are urgently needed. Here, we describe the interaction of the atypically C5alpha-methyl-substituted carbapenem, NA-1-157, with the GES-5 carbapenemase. MICs of this compound against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii producing the enzyme were reduced 4-16-fold when compared to MICs of the commercial carbapenems, reaching clinically sensitive breakpoints. When NA-1-157 was combined with meropenem, a strong synergistic effect was observed. Kinetic and ESI-LC/MS studies demonstrated that NA-1-157 is a potent inhibitor of GES-5, with a high inactivation efficiency of (2.9 +/- 0.9) x 10(5) M(-1) s(-1). Acylation of GES-5 by NA-1-157 was biphasic, with the fast phase completing within seconds, and the slow phase taking several hours and likely proceeding through a reversible tetrahedral intermediate. Deacylation was extremely slow (k(3) = (2.4 +/- 0.3) x 10(-7) s(-1)), resulting in a residence time of 48 +/- 6 days. MD simulation of the GES-5-meropenem and GES-5-NA-1-157 acyl-enzyme complexes revealed that the C5alpha-methyl group in NA-1-157 sterically restricts rotation of the 6alpha-hydroxyethyl group preventing ingress of the deacylating water into the vicinity of the scissile bond of the acyl-enzyme intermediate. These data demonstrate that NA-1-157 is a potent irreversible inhibitor of the GES-5 carbapenemase.

Restricted Rotational Flexibility of the C5alpha-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.,Stewart NK, Toth M, Quan P, Beer M, Buynak JD, Smith CA, Vakulenko SB ACS Infect Dis. 2024 Apr 12;10(4):1232-1249. doi: 10.1021/acsinfecdis.3c00683. , Epub 2024 Mar 21. PMID:38511828^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.