The new tuberculosis drug Perchlozone® shows cross-resistance with thiacetazone

Int J Antimicrob Agents. 2015 Apr;45(4):430-3. doi: 10.1016/j.ijantimicag.2014.12.026. Epub 2015 Feb 3.

Abstract

Perchlozone(®) (PCZ), a new thiosemicarbazone developed by JSC Pharmasyntez (Moscow, Russia) for the treatment of tuberculosis (TB), was approved for use against multidrug-resistant disease in Russia in 2012. The mechanism of action of the drug is unknown. A well-studied thiosemicarbazone is the old TB drug thiacetazone (TAC). It has a narrow spectrum and inhibits the FASII dehydratase complex HadABC, which is involved in cell wall biosynthesis in Mycobacterium tuberculosis. TAC is a prodrug, requiring activation by the monooxygenase EthA. In this study, a comparative in vitro analysis of both drugs was performed. The two compounds had an identical spectrum of activity, spontaneous resistant mutants showed cross-resistance, and resistance was mapped to HadABC and EthA. These results suggest that PCZ, like TAC, is a prodrug and that both drugs share EthA as an activating enzyme and HadABC as their principal target.

Keywords: EthA; HadABC; Perchlozone(®); Thiosemicarbazone; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Drug Resistance, Bacterial*
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Oxidoreductases / genetics
  • Thioacetazone / pharmacology*
  • Thiosemicarbazones / pharmacology*

Substances

  • Antitubercular Agents
  • Thiosemicarbazones
  • Oxidoreductases
  • ethA protein, Mycobacterium tuberculosis
  • Thioacetazone