Decarboxylation of the Catalytic Lysine Residue by the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase

Toth, Marta; Stewart, Nichole K.; Maggiolo, Ailiena O.; Quan, Pojun; Khan, Md Mahbub Kabir; Buynak, John D.; Smith, Clyde A.; Vakulenko, Sergei B.

doi:10.1021/acsinfecdis.4c00671

Decarboxylation of the Catalytic Lysine Residue by the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase

Journal Article · Tue Nov 26 23:00:00 EST 2024 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.4c00671· OSTI ID:2583232

Toth, Marta ^[1]; Stewart, Nichole K. ^[1]; Maggiolo, Ailiena O. ^[2]; Quan, Pojun ^[3]; Khan, Md Mahbub Kabir ^[3]; ^[3]; ^[4]; ^[1]

University of Notre Dame, IN (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Southern Methodist Univ., Dallas, TX (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Stanford Univ., CA (United States)

Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. Acinetobacter baumannii is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D β-lactamases, which have dramatically diminished available therapeutic options. Thus, new antibiotics that are active against multidrug-resistantA. baumannii and carbapenemase inhibitors are urgently needed. Here we report characterization of the interaction of the C5α-methyl-substituted carbapenem NA-1-157 with one of the clinically important class D carbapenemases, OXA-58. Antibiotic susceptibility testing shows that the compound is more potent than commercial carbapenems against OXA-58-producingA. baumannii, with a clinically sensitive MIC value of 1 μg/mL. Kinetic studies demonstrate that NA-1-157 is a very poor substrate of the enzyme due mainly to a significantly reduced deacylation rate. Mass spectrometry analysis shows that inhibition of OXA-58 by NA-1-157 proceeds through both the classical acyl-enzyme intermediate and a reversible covalent species. Time-resolved X-ray crystallographic studies reveal that upon acylation of the enzyme, the compound causes progressive decarboxylation of the catalytic lysine residue, thus severely impairing deacylation. Overall, this study demonstrates that the carbapenem NA-1-157 is highly resistant to degradation by the OXA-58 carbapenemase.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2583232

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 12 Vol. 10; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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