Molecular basis of selective inhibition and slow reversibility of avibactam against class D carbapenemases: A structure-guided study of OXA-24 and OXA-48

Sushmita D. Lahiri, Stefano Mangani, Haris Jahić, Manuela Benvenuti, Thomas F. Durand-Reville, Filomena De Luca, David E. Ehmann, Gian Maria Rossolini, Richard A. Alm, Jean Denis Docquier

Research output: Contribution to journalArticlepeer-review

Abstract

The Class D (or OXA-type) β-lactamases have expanded to be the most diverse group of serine β-lactamases with a highly heterogeneous β-lactam hydrolysis profile and are typically resistant to marketed β-lactamase inhibitors. Class D enzymes are increasingly found in multidrug resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and various species of the Enterobacteriaceae and are posing a serious threat to the clinical utility of β-lactams including the carbapenems, which are typically reserved as the drugs of last resort. Avibactam, a novel non-β-lactam β-lactamase inhibitor, not only inhibits all class A and class C β-lactamases but also has the promise of inhibition of certain OXA enzymes, thus extending the antibacterial activity of the β-lactam used in combination to the organisms that produce these enzymes. X-ray structures of OXA-24 and OXA-48 in complex with avibactam revealed the binding mode of this inhibitor in this diverse class of enzymes and provides a rationale for selective inhibition of OXA-48 members. Additionally, various subunits of the OXA-48 structure in the asymmetric unit provide snapshots of different states of the inhibited enzyme. Overall, these data provide the first structural evidence of the exceptionally slow reversibility observed with avibactam in class D β-lactamases. Mechanisms for acylation and deacylation of avibactam by class D enzymes are proposed, and the likely extent of inhibition of class D β-lactamases by avibactam is discussed.

Original languageEnglish
Pages (from-to)591-600
Number of pages10
JournalACS Chemical Biology
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Medicine(all)

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