6QWC

Molecular Basis of Class A beta-Lactamase Inhibition by Relebactam.

(2019) Antimicrob Agents Chemother 63

• PubMed: 31383664 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1128/AAC.00564-19
• Primary Citation of Related Structures:  
  6QW7, 6QW8, 6QW9, 6QWA, 6QWB, 6QWC, 6QWD, 6QWE


• PubMed 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 [IC ₅₀ ]). 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.

   View More

---

Organizational Affiliation: 

School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom.