JBC:一种抗结核新药可有效对付潜伏结核病菌


发布者:新华网 发布时间:2008-9-16

美国《生物化学杂志》12日发表的研究结果表明,一种正在开发中的新药可有效杀死潜伏在机体内的结核病菌,有望为结核病治疗提供一种有力的新手段。


美国强生公司的研究人员说,他们正在开发的这种新药编号为R207910。研究人员指出,尽管结核病的治疗近年来取得了一些进展,但这种疾病依然对人类构成严峻威胁。这是因为目前艾滋病病毒携带者往往同时感染结核病菌,耐药性结核病菌也在不断增多。结核病菌能潜伏在人的肺部,病菌携带者没有明显症状,但随时都有发病的危险。


新药R207910的最大特点是能以潜伏的结核病菌为目标,有效杀死病菌。研究人员在实验室中以不同潜伏模式的结核病菌为对象进行了测试。结果发现,这种药物能通过切断病菌的能量供应达到杀菌效果。


三磷酸腺苷(ATP)被称为细胞的能量“通货”,是生物体新陈代谢所需能量的直接来源。这种新药的目标就是结核病菌细胞合成ATP过程中非常关键的一种合酶。针对处于活跃状态并不断复制的结核病菌,这种药物能通过控制合酶来阻断病菌的能量供应,从而抵抗结核病菌。


实验结果证明,这种新药可以杀死机体内95%以上的潜伏结核病菌,而目前常用的抗结核药物对潜伏结核病菌基本不起作用。研究还发现,与活跃的结核病菌相比,这种药物对付潜伏病菌似乎更加拿手。这意味着,该药将来有望成为抗结核药物中的“奇兵”,有效地帮助改善结核病治疗方案,缩短治疗时间。


研究人员目前正以多耐药结核病菌为对象进行这种新药的临床研究,以进一步验证上述实验结果。研究人员建议,在研究如何对付其他顽固的病菌感染时,也应把ATP合酶作为一个重要的目标。


J. Biol. Chem., Vol. 283, Issue 37, 25273-25280, September 12, 2008
Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis
Anil Koul, Luc Vranckx, Najoua Dendouga, Wendy Balemans, Ilse Van den Wyngaert, Karen Vergauwen, Hinrich W. H. G?hlmann, Rudy Willebrords, Alain Poncelet?, Jerome Guillemont?, Dirk Bald, and Koen Andries
From the Departments of Antimicrobial Research and Functional Genomics, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium,¶Pharmaceutical Research and Development, Tibotec NV, Johnson & Johnson, Campus de Maigremont-BP615, F-27106 Val de Reuil Cedex, France, and the||Department of Structural Biology, VU University Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands

An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment.