The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis.

 描述（由申请人提供）：每年，结核分枝杆菌感染导致800多万新发结核病（TB）病例和近200万例死亡。吡嗪酰胺（PZA）是一种一线抗结核药物，预计将成为未来结核病治疗方案中不可替代的组成部分。尽管PZA的临床应用已经超过60年，但其活性的机制基础尚未得到解决。以往的研究表明，PZA是一种前药，通过M.结核酰胺酶PncA的功能缺失突变导致了绝大多数PZA耐药。PZA对M.在实验室培养中，这种药物介导人类和动物感染模型中杆菌的灭菌。因此，PZA对M的作用增强涉及一种尚未确定的宿主依赖性活性。结核我们这个项目的长期目标是确定PZA对M.结核已知的是 POA，而不是PZA，与生物催化和氧化应激中涉及的几种二价金属形成络合物，但这种相互作用与PZA作用的相关性尚未探讨。我们正在使用多学科的方法来解决这一假设，即PZA治疗对M.结核这些研究将为PZA的作用机制提供新的线索，并解释M。结核病PZA暴露在文化与哺乳动物系统。解决PZA作用的基础将指导发现对M具有保守或改善作用的新药物。结核病，以对抗耐药性。

 DESCRIPTION (provided by applicant): Each year, Mycobacterium tuberculosis infections contribute to over 8 million new cases of tuberculosis (TB) and nearly 2 million deaths. Pyrazinamide (PZA) is a first-line sterilizing anti-tubercular drug that is anticipated to be an irreplaceable component of future TB treatment regimens. Despite more than 60 years of clinical use of PZA, the mechanistic basis for its activity has yet to be resolved. Previous studie have demonstrated that PZA is a pro-drug that is converted to the active form of pyrazinoic acid (POA) by the M. tuberculosis amidase PncA, and that loss of function mutations in pncA account for the vast majority of PZA resistance. In addition, while PZA is only conditionally bacteriostatic for M. tuberculosis in laboratory culture, this drug mediates sterilization of bacili in humans and in animal models of infection. Thus, there is an as yet undefined host-dependent activity involved in potentiation of PZA action on M. tuberculosis. Our long-term goal for this project is to define the mechanistic basis for PZA action against M. tuberculosis. It is known that POA, but not PZA, forms complexes with several divalent metals involved in biocatalysis and oxidative stress, yet the relevance of this interaction for PZA action has not been explored. We are using a multidisciplinary approach to address the hypothesis that PZA treatment has a profound impact on metal homeostasis and oxidative stress in M. tuberculosis. These studies will shed new light on the poorly understood mode of action of PZA and stand to explain the dichotomous outcome of M. tuberculosis PZA exposure in culture versus in a mammalian system. Resolving the basis for PZA action will guide the discovery of novel agents with a conserved or improved action against M. tuberculosis to counter drug resistance.