Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome

J Med Chem. 2019 Oct 24;62(20):9246-9253. doi: 10.1021/acs.jmedchem.9b01187. Epub 2019 Oct 15.

Abstract

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

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.

MeSH terms

  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Reactive Nitrogen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Proteasome Inhibitors
  • Reactive Nitrogen Species