Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02071-18. doi: 10.1128/AAC.02071-18. Print 2019 Apr.

Abstract

AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline antituberculosis agent isoniazid.

Keywords: C3HeB/FeJ mice; antimicrobial resistance; caseum; drug development; isoniazid; necrotic lesions; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Aza Compounds / pharmacology*
  • Bacterial Load / drug effects
  • Boron Compounds / pharmacology*
  • Disease Models, Animal
  • Drug Development
  • Female
  • Hydrocarbons, Fluorinated / pharmacology*
  • Inhibins / antagonists & inhibitors*
  • Isoniazid / pharmacology
  • Lung / pathology
  • Mice
  • Mice, Inbred C3H
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / microbiology

Substances

  • AN12855
  • Antitubercular Agents
  • Aza Compounds
  • Boron Compounds
  • Hydrocarbons, Fluorinated
  • inhibin-alpha subunit
  • Inhibins
  • Isoniazid