The impact of pyrazinamide on metabolism in Mycobacterium tuberculosis.

吡嗪酰胺对结核分枝杆菌代谢的影响。

• 批准号: 9212104
• 负责人: ANTHONY D BAUGHN
• 金额: $ 38.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212104
• 关键词: Acids; Address; Alpha Cell; Animal Model; Antitubercular Agents; Bacillus (bacterium); Cell-Free System; Cessation of life; Chelating Agents; Chemosensitization; Clinical; Complex; Data; Diffusion; Drug resistance; Drug usage; Enzymes; Future; Goals; Homeostasis; Human; Hydrocarbons; Hydrogen Peroxide; Hydroxyl Radical; Infection; Knowledge; Laboratory culture; Light; Mass Spectrum Analysis; Mediating; Metabolic Pathway; Metabolism; Metalloproteins; Metals; Modeling; Mycobacterium tuberculosis; Oranges; Outcome; Oxidative Stress; Peroxides; Pharmaceutical Preparations; Predisposition; Prodrugs; Pyrazinamide; Pyrazinamide resistance; Research; Respiratory Burst; Role; Sterilization; System; Time; Treatment Efficacy; Treatment Protocols; Tuberculosis; amidase; bactericide; base; biological adaptation to stress; chelation; design; divalent metal; drug discovery; guided inquiry; improved; interdisciplinary approach; killings; loss of function mutation; metalloenzyme; mouse model; next generation; novel; novel therapeutics; oxidation; oxidative damage; public health relevance; pyrazinoic acid; resistant strain; tuberculosis drugs; tuberculosis treatment

 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.

 描述（由申请人提供）：每年，结核分枝杆菌感染导致超过 800 万新发结核病 (TB) 病例和近 200 万人死亡。吡嗪酰胺（PZA）是一线杀菌抗结核药物，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 的临床应用已有 60 多年的历史，但其活性的机制基础尚未得到解决。先前的研究表明，PZA 是一种前药，可被结核分枝杆菌酰胺酶 PncA 转化为活性形式的吡嗪酸 (POA)，并且 pncA 的功能缺失突变导致绝大多数 PZA 耐药。此外，虽然 PZA 仅对实验室培养中的结核分枝杆菌有条件抑菌，但该药物可介导人类和感染动物模型中的杆菌灭菌。因此，PZA 对结核分枝杆菌作用的增强涉及尚未确定的宿主依赖性活性。我们该项目的长期目标是确定 PZA 对抗结核分枝杆菌作用的机制基础。据了解 POA（而非 PZA）与几种参与生物催化和氧化应激的二价金属形成复合物，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方法来解决 PZA 治疗对结核分枝杆菌的金属稳态和氧化应激具有深远影响的假设。这些研究将为人们对 PZA 的作用模式了解甚少提供新的线索，并解释在培养物和哺乳动物系统中结核分枝杆菌 PZA 暴露的二分结果。解决 PZA 作用的基础将指导发现具有保守或改进的抗结核分枝杆菌作用以对抗耐药性的新药物。