Ceftazidime–Avibactam Resistance Mutations V240G, D179Y, and D179Y/T243M in KPC-3 β-Lactamase Do Not Alter Cefpodoxime–ETX1317 Susceptibility
Year: 2020
Type: article
Abstract: Mutations in KPC-2 and KPC-3 β-lactamase can confer resistance to the β-lactam/β-lactamase inhibitor antibacterial intravenous drug combination ceftazidime–avibactam, introduced in 2015. Avibactam was the first of the diazabicyclooctane class of non-β-lactam β-lactamase inhibitors to be approved for clinical use. The orally bioavailable prodrug ETX0282 of the diazabicyclooctane β-lactamase inhibitor ETX1317 is in clinical development in combination with the oral β-lactam prodrug cefpodoxime proxetil for use against complicated urinary tract infections. We investigated the effects of 3 ceftazidime–avibactam resistance mutations in KPC-3 (V240G, D179Y, and D179Y/T243M) on the ability of ETX1317 to overcome KPC-3-induced cefpodoxime resistance. Isogenic Escherichia coli strains, each expressing the wild-type or a mutant KPC-3 at similar levels, retained susceptibility to cefpodoxime–ETX1317 (1:2) with essentially identical minimal inhibitory concentrations of 0.125–0.25 μg/mL cefpodoxime. The KPC-3 mutations had little or no effect on the kinact/Ki values for inhibition by each of 3 diazabicyclooctanes: avibactam, durlobactam (ETX2514), and ETX1317. The KM values for hydrolysis of cefpodoxime were similar for all 4 variants, but the kcat values of the D179Y and D179Y/T243M variants were much lower than those of the wild-type and V240G mutant enzymes. All 4 KPC-3 variants formed stable, reversibly covalent complexes with ETX1317, but dissociation of ETX1317 was much slower from the D179Y and D179Y/T243M mutants than from the wild-type and V240G mutant enzymes. Thus, the KPC-3 variants examined here that cause resistance to ceftazidime–avibactam do not cause resistance to cefpodoxime–ETX1317.
Source: ACS Infectious Diseases
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
OpenAlex ID: W3111856782