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 β-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 β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 104 M−1. sec−1, and prolonged active site residence times (t1/2, 5 to 46 min). 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 4 μg/mL) in isogenic strains of E. coli expressing class A, C or D β-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 = 0.25 μg/mL), KPCs (MIC90 = 1 μg/mL), class C cephalosporinases (MIC90 = 1 μg/mL) and OXA-48-type carbapenemases (MIC90 = 1 μg/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 (ED50, >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by K. pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.
Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis