2. Academic Validation
  3. Structural role of K224 in taniborbactam inhibition of NDM-1

Structural role of K224 in taniborbactam inhibition of NDM-1

  • Antimicrob Agents Chemother. 2024 Jan 4:e0133223. doi: 10.1128/aac.01332-23.
Daisuke Ono # 1 2 3,  Maria F Mojica # 2 3 4,  Christopher R Bethel 3,  Yoshikazu Ishii 5,  Salvador I Drusin 6 7,  Diego M Moreno 6 7,  Alejandro J Vila 6 8,  Robert A Bonomo 1 2 3 4 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 2 Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 3 Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • 4 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA.
  • 5 Department of Microbiology and Infectious Disease, Toho University School of Medicine, Tokyo, Japan.
  • 6 Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
  • 7 Instituto de Química Rosario (IQUIR), CONICET, Rosario, Argentina.
  • 8 Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Universidad Nacional de Rosario, Rosario, Argentina.
  • 9 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 10 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 11 Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 12 Clinician Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • # Contributed equally.
PMID: 38174924 DOI: 10.1128/aac.01332-23
Abstract

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid β-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-β-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ). We hypothesized that substitutions at K224, the homologous position in NDM-1, could impact FEP/TAN resistance. To evaluate this, a library of codon-optimized NDM K224X clones for minimum inhibitory concentration (MIC) measurements was constructed; steady-state kinetics and molecular docking simulations were next performed. Surprisingly, our investigation revealed that the addition of TAN restored FEP susceptibility only for NDM-1, as the MICs for the Other 19 K224X variants remained comparable to those of FEP alone. Moreover, compared to NDM-1, all K224X variants displayed significantly lower MICs for imipenem, tebipenem, and cefiderocol (32-, 133-, and 33-fold lower, respectively). In contrast, susceptibility to CAZ was mostly unaffected. Kinetic assays with the K224I variant, the only variant with hydrolytic activity to FEP comparable to NDM-1, confirmed that the inhibitory capacity of TAN was modestly compromised (IC50 0.01 µM vs 0.14 µM for NDM-1). Lastly, structural modeling and docking simulations of TAN in NDM-1 and in the K224I variant revealed that the hydrogen bond between TAN's carboxylate with K224 is essential for the productive binding of TAN to the NDM-1 active site. In addition to the report of NDM-9 (E149K) as FEP/TAN resistant, this study demonstrates the fundamental role of single amino acid substitutions in the inhibition of NDM-1 by TAN.

Keywords

K224; NDM-1; metallo-β-lactamase; taniborbactam; β-lactamase inhibitor.

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