Tetrazole-based inhibitors of the bacterial enzyme N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase as potential antibiotics

Bioorg Med Chem Lett. 2023 Mar 1:83:129177. doi: 10.1016/j.bmcl.2023.129177. Epub 2023 Feb 9.

Abstract

Based on a hit from a high-throughput screen, a series of phenyltetrazole amides was synthesized and assayed for inhibitory potency against DapE from Haemophilus influenzae (HiDapE). The inhibitory potency was modest but confirmed, with the most potent analog containing an aminothiazole moiety displaying an IC50 = 50.2 ± 5.0 μM. Docking reveals a potential binding mode wherein the amide carbonyl bridges both zinc atoms in the active site, and the tetrazole forms key hydrogen bonds with Arg330.

Keywords: Aminothiazole; Antibiotic; DapE; Diaminopimelate desuccinylase; Enzyme inhibition; Indoline; Ninhydrin enzyme assay; Sulfonamide; Tetrazole.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents* / pharmacology
  • Catalytic Domain
  • Diaminopimelic Acid / chemistry
  • Diaminopimelic Acid / metabolism
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Tetrazoles / chemistry
  • Zinc* / chemistry

Substances

  • Anti-Bacterial Agents
  • Diaminopimelic Acid
  • Enzyme Inhibitors
  • Zinc
  • Tetrazoles