The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters

Trends Pharmacol Sci. 2018 Jul;39(7):635-647. doi: 10.1016/j.tips.2018.03.007. Epub 2018 Apr 18.

Abstract

Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.

Keywords: inhibitor; mechanism; metallo-β-lactamase; spectroscopy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / drug effects*
  • Bacterial Proteins / metabolism
  • Catalytic Domain
  • Drug Resistance, Microbial
  • Humans
  • Models, Molecular
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / chemistry
  • beta-Lactamases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • beta-Lactamase Inhibitors
  • beta-Lactamases