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

休眠分枝杆菌耐药的分子机制及药物靶点的鉴定

• 批准号: 21590486
• 负责人: MATSUMOTO Sohkichi
• 金额: $ 2.91万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590486/
• 关键词: 感染症; 結核; 薬剤耐性; 増殖; イソニアジド; 薬剤; 化学療法; 潜在性結核; 休暇; KatG; 抗酸菌; 休眠

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.

结核病是世界范围内发现的致命传染病，仍然是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的耐受性导致治疗持续时间延长是有效TB化疗的一个问题。INH是一种前药，由分枝杆菌酶KatG激活。我们已经表明，分枝杆菌DNA结合蛋白1（MDP1），这是一个组蛋白样蛋白在分枝杆菌中保守，负调控KatG转录，并导致表型耐药性INH分枝杆菌。与野生型菌株相比，MDP1缺陷的耻垢分枝杆菌表现出KatG表达增加，并表现出增强的INH活化。MDP1的表达在稳定期增加，并赋予M的生长期依赖性耐受性。包皮垢到INH。KatG表达的调控在M.耻垢病和结核分枝杆菌复合体。人工减少牛分枝杆菌BCG中的MDP1显示导致KatG表达增加和对INH的敏感性增加。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。

项目成果

Clinical practice for the diagnosis of latent mycobacterium tuberculosis infection

潜伏结核分枝杆菌感染诊断的临床实践

• 发表时间: 2010
• 作者: Osada-Oka M;Hirayama Y;Kitada S;Tateishi Y;Maekura R;Sugimura H;Koide Y;Kobayashi K;Matsumoto S
• 通讯作者: Matsumoto S

結核菌感染における制御性T細胞の関与

调节性 T 细胞参与结核分枝杆菌感染

• 发表时间: 2010
• 作者: 尾関百合子;菅原勇;岡真優子;小林和夫;松本壮吉
• 通讯作者: 松本壮吉

Growth inhibition of HeLa cell by internalization of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) Tokyo.

通过内化牛分枝杆菌卡介苗 (BCG) 东京来抑制 HeLa 细胞的生长。

• 发表时间: 2009
• 期刊: Cancer Cell Int 9
• 作者: Kitamura;A.;S.Matsumoto.;et al.
• 通讯作者: et al.

Molecular mechanisms of latent tuberculiosis infection(LTBI) and development of diagnosis of LTBI

潜伏性结核感染（LTBI）的分子机制及LTBI诊断进展

• 发表时间: 2010
• 作者: Yanagisawa N;Haruta I;Kikuchi K;Shibata N;Yagi J;松本壮吉
• 通讯作者: 松本壮吉

人獣共通感染症, 非結核性抗酸菌症改訂版

人畜共患病、非结核分枝杆菌疾病修订版

• 发表时间: 2011
• 作者: 西内由紀子;立石善隆;山田毅;松本壮吉症;木村哲;喜田宏編集
• 通讯作者: 喜田宏編集