2. Academic Validation
  3. Inhibitor Affinity Differs among Clinical Variants of IMP Metallo- β-Lactamases: Analysis and Implications for Inhibitor Design

Inhibitor Affinity Differs among Clinical Variants of IMP Metallo- β-Lactamases: Analysis and Implications for Inhibitor Design

  • ACS Infect Dis. 2025 Aug 8;11(8):2157-2168. doi: 10.1021/acsinfecdis.5c00138.
Caitlyn A Thomas 1,  John Paul Alao 1,  Thomas Smisek 2,  Zishuo Cheng 1,  Christopher R Bethel 3,  Kundi Yang 1,  Ikponwmosa Obaseki 1,  Richard C Page 1,  Robert A Bonomo 3 4 5 6 7 8,  Peter Oelschlaeger 9,  Walter Fast 2,  Andrea N Kravats 1,  Michael W Crowder 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States.
  • 2 Department of Molecular Biosciences, The University of Texas, Austin, Texas 78712, United States.
  • 3 Medical Service, VA Northeast Ohio Health Care System Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.
  • 4 Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 45056, United States.
  • 5 Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 6 Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.
  • 7 Departments of Pharmacology, Molecular Biology & Microbiology, and Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 8 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio 44106, United States.
  • 9 Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California 91766, United States.
PMID: 40704846 DOI: 10.1021/acsinfecdis.5c00138
Abstract

β-Lactam-resistant Bacterial infections are a serious concern worldwide. A common mechanism of β-lactam resistance is the expression of β-lactamases, which are capable of hydrolyzing the β-lactam bond in the most commonly used β-lactam Antibiotics. Metallo-β-lactamases (MBLs) utilize 1 or 2 zinc ions for catalysis. One of the three most clinically relevant MBLs is Imipenemase (IMP). An important potential way to combat MBLs is to use an inhibitor in combination with an existing β-lactam drug. The current study investigates the mechanism of inhibition of preclinical boronic acid β-lactamase inhibitor RPX 7546 and mercaptomethyl bisthiazolidine D-CS319, which are two previously reported MBL inhibitors, with IMP-1 and its variant IMP-78 (V67F/S262G), chosen due to its improved efficiency hydrolyzing carbapenem β-lactams. A combination of analytical and biochemical experiments and in silico modeling collectively offer a comprehensive understanding of the mechanism of inhibition by these two inhibitors. Our studies show that RPX 7546 is a less effective inhibitor of IMP-78, compared to IMP-1, while D-CS319 shows equally effective inhibition of both Enzymes. The findings can be explained in light of the evolution of IMP-78 to overcome structural differences of substrates. Studying inhibitors with variants of clinically relevant MBLs is an area that is growing in importance in the literature. The findings of the current study highlight its significance and the urgent need for the discovery of an MBL inhibitor for clinical use.

Keywords

antibiotic resistance; imipenemase; mechanism of inhibition; metallo-β-lactamase; metallo-β-lactamase inhibitors.

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