Abstract
β-Lactamase production is the major β-lactam resistance mechanism in Gram-negative bacteria. β-Lactamase inhibitors (BLIs) efficacious against serine β-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI, is in phase 3 clinical trials in combination with imipenem for the treatment of infections by multidrug-resistant Enterobacteriaceae We show that relebactam inhibits five clinically important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e., the extended-spectrum β-lactamases L2 (inhibition constant 3 μM) and CTX-M-15 (21 μM) and the carbapenemases KPC-2, -3, and -4 (1 to 5 μM). Against purified class A SBLs, relebactam is an inferior inhibitor compared with the clinically approved DBO avibactam (9- to 120-fold differences in half maximal inhibitory concentration [IC50]). MIC assays indicate relebactam potentiates β-lactam (imipenem) activity against KPC-producing Klebsiella pneumoniae, with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against Stenotrophomonas maltophilia K279a. X-ray crystal structures of relebactam bound to CTX-M-15, L2, KPC-2, KPC-3, and KPC-4 reveal its C2-linked piperidine ring can sterically clash with Asn104 (CTX-M-15) or His/Trp105 (L2 and KPCs), rationalizing its poorer inhibition activity than that of avibactam, which has a smaller C2 carboxyamide group. Mass spectrometry and crystallographic data show slow, pH-dependent relebactam desulfation by KPC-2, -3, and -4. This comprehensive comparison of relebactam binding across five clinically important class A SBLs will inform the design of future DBOs, with the aim of improving clinical efficacy of BLI-β-lactam combinations.
Highlights
ABSTRACT -Lactamase production is the major -lactam resistance mechanism in Gram-negative bacteria. -Lactamase inhibitors (BLIs) efficacious against serine -lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required
An avibactam:aztreonam combination proved successful in the treatment of several S. maltophilia strains [30]; we investigate whether this activity is reflected with a relebactam:aztreonam combination
We demonstrate that relebactam, the most recent DBO to enter phase 3 clinical trials, inhibits the diverse, clinically relevant class A SBLs L2 and CTX-M-15 and three KPC variants, albeit at reduced potency compared with avibactam
Summary
ABSTRACT -Lactamase production is the major -lactam resistance mechanism in Gram-negative bacteria. -Lactamase inhibitors (BLIs) efficacious against serine -lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. We show that relebactam inhibits five clinically important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e., the extended-spectrum -lactamases L2 (inhibition constant 3 M) and CTX-M-15 (21 M) and the carbapenemases KPC-2, -3, and -4 (1 to 5 M). Of particular clinical importance is the widely disseminated class A SBLs, including the mobile, plasmid-encoded extended-spectrum CTX-M and carbapenem-hydrolyzing KPC families (both produced in opportunistic Gram-negative bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli [3, 4]), as well as chromo-. Some class A SBLs have accumulated mutations resulting in inhibitor resistance [11], while enzymes such as KPC show reduced susceptibility to inhibition [12] These observations highlight the need for novel BLIs effective against a wider range of -lactamases
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