title: The new tuberculosis drug Perchlozone® shows cross-resistance with thiacetazone.
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.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Block MD4A, Singapore 117545, Republic of Singapore.
authors.forename: Pooja
authors.initials: P
authors.lastname: Gopal
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Block MD4A, Singapore 117545, Republic of Singapore. Electronic address: thomas_dick@nuhs.edu.sg.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010088:Oxidoreductases / Q000235:genetics; D013828:Thioacetazone / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D013882:Thiosemicarbazones; D010088:Oxidoreductases; C480352:ethA protein, Mycobacterium tuberculosis; D013828:Thioacetazone
keywords: EthA; HadABC; Perchlozone(®); Thiosemicarbazone; Tuberculosis