The sequence-activity relationship between metallo-β-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary adaptation to meropenem exposure

Antimicrob Agents Chemother. 2012 Dec;56(12):6403-6. doi: 10.1128/AAC.01440-12. Epub 2012 Sep 24.

Abstract

Metallo-β-lactamases are important determinants of antibacterial resistance. In this study, we investigate the sequence-activity relationship between the closely related enzymes IMP-1, IMP-6, and IMP-25. While IMP-1 is the more efficient enzyme across the overall spectrum of tested β-lactam antibacterial agents, IMP-6 and IMP-25 seem to have evolved to specifically inactivate the newer carbapenem meropenem. Molecular modeling indicates that the G235S mutation distinguishing IMP-25 from IMP-1 and IMP-6 may affect enzyme activity via Asn233.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Biological / genetics*
  • Adaptation, Biological / physiology
  • Amino Acid Sequence
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / drug effects
  • Bacterial Proteins / genetics*
  • Biological Evolution
  • Drug Resistance, Bacterial / genetics*
  • Kinetics
  • Meropenem
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Thienamycins / pharmacology*
  • beta-Lactamases / drug effects*
  • beta-Lactamases / genetics*
  • beta-Lactams / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Thienamycins
  • beta-Lactams
  • beta-lactamase IMP-1
  • beta-Lactamases
  • beta-lactamase IMP-25, Pseumonas aeruginosa
  • Meropenem