Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase

Stewart, Nichole K.; Toth, Marta; Quan, Pojun; Beer, Michael; Buynak, John D.; Smith, Clyde A.; Vakulenko, Sergei B.

doi:10.1021/acsinfecdis.3c00683

Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase

Journal Article · Thu Mar 21 00:00:00 EDT 2024 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.3c00683· OSTI ID:2337591

Stewart, Nichole K. ^[1]; Toth, Marta ^[2]; Quan, Pojun ^[3]; ^[4]; ^[3]; ^[5]; ^[2]

University of Notre Dame, IN (United States); University of Notre Dame
University of Notre Dame, IN (United States)
Southern Methodist University, Dallas, TX (United States)
University of Bristol (United Kingdom)
Stanford University, Menlo Park, CA (United States); Stanford University, CA (United States)

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 C5α-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) × 105 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 (k₃ = (2.4 ± 0.3) × 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 C5α-methyl group in NA-1- 157 sterically restricts rotation of the 6α-hydroxyethyl group preventing ingress of the deacylating water into the vicinity of the scissile bond of the acyl-enzyme intermediate. Furthermore, these data demonstrate that NA-1-157 is a potent irreversible inhibitor of the GES-5 carbapenemase.

View Accepted Manuscript (DOE)

Research Organization:: University of Notre Dame, IN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2337591

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 4 Vol. 10; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase

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