| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Research Abstract |
Tuberculosis is deadly infectious diseases found worldwide and remains a leading public health problem. Although isoniazid(INH) is a key drug for the treatment of tuberculosis(TB), tolerance against INH that causes prolonged treatment duration is a concern for effective TB chemotherapy. INH is a prodrug and is activated by the mycobacterial enzyme, KatG. We have shown 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 to the wild-type strain. Expression of MDP1 was increased in the stationary phase and conferred growth phase-dependent tolerance of M. smegmatis to INH. Regulation of KatG expression is conserved among 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 demonstrate the phenotypic tolerance mechanism to INH of mycobacteria by a histone-like protein.
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