Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii

Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01576-17. doi: 10.1128/AAC.01576-17. Print 2018 Feb.

Abstract

The novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistant Acinetobacter baumannii The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10-10 to <9.0 × 10-10 at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to β-lactamase inhibition, ETX2514 may enhance sulbactam activity in A. baumannii via inhibition of PBP2.

Keywords: Acinetobacter baumannii; ETX2514; antibiotic resistance; sulbactam; β-lactamase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter Infections / microbiology
  • Acinetobacter baumannii / drug effects*
  • Acinetobacter baumannii / genetics
  • Acinetobacter baumannii / isolation & purification
  • Acinetobacter baumannii / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Binding Sites
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / genetics
  • Drug Therapy, Combination
  • Gene Expression Regulation, Bacterial*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mutation
  • Penicillin-Binding Proteins / antagonists & inhibitors
  • Penicillin-Binding Proteins / chemistry
  • Penicillin-Binding Proteins / genetics
  • Penicillin-Binding Proteins / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Sulbactam / pharmacology*
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Penicillin-Binding Proteins
  • Protein Isoforms
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • durlobactam
  • Sulbactam