A novel mechanism of growth phase-dependent tolerance to isoniazid in mycobacteria

Makoto Niki, Mamiko Niki, Yoshitaka Tateishi, Yuriko Ozeki, Teruo Kirikae, Astrid Lewin, Yusuke Inoue, Makoto Matsumoto, John L. Dahl, Hisashi Ogura, Kazuo Kobayashi, Sohkichi Matsumoto

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Tuberculosis remains one of the most deadly infectious diseases worldwide and is a leading public health problem. Although isoniazid (INH) is a key drug for the treatment of tuberculosis, tolerance to INH necessitates prolonged treatment, which is a concern for effective tuberculosis chemotherapy. INH is a prodrug that is activated by the mycobacterial enzyme, KatG. Here, we show that mycobacterial DNA-binding protein 1 (MDP1), which is a histone-like protein conserved in mycobacteria, negatively regulates katG transcription and leads to phenotypic tolerance to INH in mycobacteria. Mycobacterium smegmatis deficient for MDP1 exhibited increased expression of KatG and showed enhanced INH activation compared with the wild-type strain. Expression of MDP1 was increased in the stationary phase and conferred growth phase-dependent tolerance to INH in M. smegmatis. Regulation of KatG expression is conserved between M. smegmatis and Mycobacterium tuberculosis complex. Artificial reduction of MDP1 in Mycobacterium bovis BCG was shown to lead to increased KatG expression and susceptibility to INH. These data suggest a mechanism by which phenotypic tolerance to INH is acquired in mycobacteria.

Original languageEnglish (US)
Pages (from-to)27743-27752
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number33
DOIs
StatePublished - Aug 10 2012

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