Molecular mechanism of drug tolerance in dormant mycobacteria and identification of the drug target

结核病是世界范围内发现的致命传染病，仍然是一个主要的公共卫生问题。尽管异烟肼（INH）是治疗结核病（TB）的关键药物，但对INH的耐受性会导致治疗时间延长，这是结核病有效化疗的一个问题。INH是一种前药，由分枝杆菌酶KatG激活。我们已经证明，分枝杆菌dna结合蛋白1（MDP1）是一种保守于分枝杆菌中的组蛋白样蛋白，它负调控KatG转录并导致分枝杆菌对INH的表型耐受。与野生型菌株相比，缺乏MDP1的耻垢分枝杆菌表现出KatG表达增加和INH激活增强。MDP1的表达在固定期增加，并赋予耻毛分枝杆菌对INH的生长阶段依赖性耐受性。KatG的表达调控在耻毛分枝杆菌和结核分枝杆菌复合体中是保守的。牛分枝杆菌中MDP1的人工减少导致KatG表达增加和对INH的易感性。这些数据证明了分枝杆菌通过组蛋白样蛋白对INH的表型耐受机制。

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.