Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2018 Jan 25;62(2):e02222-17. doi: 10.1128/AAC.02222-17. Print 2018 Feb.

Abstract

IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Mycobacterium tuberculosis Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the katG gene. The katG(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.

Keywords: MIC; antibiotic resistance; spontaneous mutants; tuberculosis; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / genetics
  • DNA, Bacterial / genetics
  • Drug Resistance, Bacterial / drug effects*
  • Drug Resistance, Bacterial / genetics
  • Ferrous Compounds / pharmacology*
  • Humans
  • Isoniazid / analogs & derivatives*
  • Isoniazid / pharmacology
  • Mutation / genetics
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Whole Genome Sequencing / methods

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • DNA, Bacterial
  • Ferrous Compounds
  • pentacyano(isoniazid)ferrate(II)
  • Isoniazid