The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis.

 描述(申请人提供)：每年，结核分枝杆菌感染导致800多万新的结核病病例和近200万人死亡。吡嗪酰胺(PZA)是一种一线杀菌抗结核药物，有望成为未来结核病治疗方案中不可替代的成分。尽管PZA的临床应用已有60多年的历史，但其活性的机制基础仍未得到解决。以往的研究表明，PZA是一种被结核分枝杆菌酰胺酶pncA转化为活性形式的吡嗪酸(POA)的前体药物，pncA功能突变的缺失是PZA耐药性的主要原因。此外，虽然PZA在实验室培养中只对结核分枝杆菌有条件地抑制细菌，但这种药物在人类和动物感染模型中介导了杆菌的灭菌。因此，有一种尚未确定的宿主依赖活性参与了PZA对结核分枝杆菌的增强作用。我们这个项目的长期目标是确定PZA对结核分枝杆菌采取行动的机制基础。众所周知， POA而不是PZA与几种参与生物催化和氧化应激的二价金属形成络合物，但这种相互作用与PZA作用的相关性尚未被探索。我们正在使用多学科的方法来解决这样的假设，即PZA治疗对结核分枝杆菌的金属动态平衡和氧化应激有深远的影响。这些研究将为了解PZA鲜为人知的作用模式提供新的线索，并将解释结核分枝杆菌PZA在培养系统和哺乳动物系统中暴露的两种结果。解决PZA作用的基础将指导发现对结核分枝杆菌具有保守或改进作用的新药物来对抗耐药性。

 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.