Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA

Tuberculosis (Edinb). 2017 Dec:107:133-136. doi: 10.1016/j.tube.2017.09.003. Epub 2017 Sep 13.

Abstract

Isoniazid inhibits Mycobacterium tuberculosis InhA and is a key component of drug regimens that treat tuberculosis. However, the high rate of resistance against isoniazid is a contributing factor to the emergence of multi-drug resistance strains of M. tuberculosis. The 4-hydroxy-2-pyridine NITD-916 is a direct inhibitor of M. tuberculosis InhA that has comparable efficacy to isoniazid in mouse models of TB infection but a lower frequency of resistance. To characterize resistance mechanisms against NITD-916 we isolated resistant mutants in H37Rv (Euro-American lineage) and HN878 (East-Asian lineage) strains of M. tuberculosis. The resistance frequency was similar in both strains. Mutations were identified in residues within or near to the active of InhA or in the fabG1inhA promoter region. All mutants were resistant to NITD-916 but were not cross resistant to isoniazid, despite homology to SNPs identified in isoniazid resistant clinical isolates.

Keywords: Antimicrobial; InhA; Isoniazid; Mycobacteria; Resistance.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Drug Resistance, Bacterial* / genetics
  • Genotype
  • Isoniazid / pharmacology
  • Microbial Sensitivity Tests
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / genetics
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Pyridines / pharmacology*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Pyridines
  • 2,4-dihydroxypyridine
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • Isoniazid