A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Cell Chem Biol. 2020 May 21;27(5):560-570.e10. doi: 10.1016/j.chembiol.2020.02.007. Epub 2020 Mar 19.

Abstract

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

Keywords: JSF-3285; KasA; Mycobacterium tuberculosis; antitubercular; pharmacokinetics; structure-based design.

Publication types

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

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Animals
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Mice
  • Models, Molecular
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Tuberculosis / drug therapy*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase