Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Nat Chem. 2022 Jan;14(1):15-24. doi: 10.1038/s41557-021-00831-x. Epub 2021 Dec 13.

Abstract

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gram-Negative Bacteria / drug effects
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Protein Binding
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / metabolism
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactams / metabolism*

Substances

  • beta-Lactamase Inhibitors
  • beta-Lactams