| Autor: |
Chatwin CL; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Hamrick JC; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Trout REL; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Myers CL; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Cusick SM; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Weiss WJ; UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, USA., Pulse ME; UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, USA., Xerri L; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Burns CJ; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Moeck G; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Daigle DM; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., John K; MTF Biologics, Edison, New Jersey, USA., Uehara T; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA., Pevear DC; Venatorx Pharmaceuticals, Incorporated, Malvern, Pennsylvania, USA. |
| Abstrakt: |
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 10 4 M -1 · sec -1 , and prolonged active site residence times ( t 1/2 , 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 Escherichia 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 (MIC 90 , 0.25 μg/ml), KPCs (MIC 90 , 1 μg/ml), class C cephalosporinases (MIC 90 , 1 μg/ml), and OXA-48-type carbapenemases (MIC 90 , 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 (50% effective dose [ED 50 ], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED 50 , 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 . |
