Microbiological characterization of VNRX-5236, a broad-spectrum b-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of enterobacterales expressing extended-spectrum b-lactamases and serine carbapenemases

Cassandra L. Chatwin, Jodie C. Hamrick, Robert E.L. Trout, Cullen L. Myers, Susan M. Cusick, William J. Weiss, Mark E. Pulse, Luigi Xerri, Christopher J. Burns, Gregory Moeck, Denis M. Daigle, Kaitlyn John, Tsuyoshi Uehara, Daniel C. Pevear

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid b-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum b-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine b-lactamases, with inactivation efficiencies on the order of 104 M21 · sec21, and prolonged active site residence times (t1/2, 5 to 46min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4mg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D b-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90, 0.25mg/ml), KPCs (MIC90, 1mg/ml), class C cephalosporinases (MIC90, 1mg/ml), and OXA-48-type carbapenemases (MIC90, 1mg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4 the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (50% effective dose [ED50], .128mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED50, 12.9mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.

Original languageEnglish
Article numbere00552
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • Ceftibuten
  • Enterobacterales
  • Oral antibiotics
  • VNRX-5236 etzadroxil
  • VNRX-7145

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