Unraveling the Origin of Pyrazinamide's Synergy with other anti-TB Drugs

 描述（由申请人提供）：需要能够解决日益严重的耐多药结核病（MDR-TB）和其他抗菌药物耐药性问题的新型、更有效和更安全的药物，需要制定最终目标为鉴定显示有利理化性质、效力和毒性的先导药物的策略。一个成功的策略是建立在成熟的一线药物上，但对作用或协同作用机制知之甚少。在本提案中，我们重点关注吡嗪酰胺（PZA），这是一种与几乎所有其他抗结核药物具有协同作用的药物，并被纳入目前的抗结核治疗方案，作为将治疗时间从9个月缩短到6个月的一种手段。然而，这种药物的作用方式仍然存在争议，没有数据解释这种药物与其他药物之间强大协同作用背后的机制。最近的研究已经提出了在抑制反式翻译和/或破坏细菌ATP合成中的作用。我们的抗结核药物在第二阶段的临床试验中， SQ-109和类似物使我们得出结论，除了酶抑制外，质子动力（PMF）的破坏对这些化合物的功效也很重要。因此，我们假设PMF的破坏在PZA的协同特性中起着重要作用。在这个项目中，我们 建议剖析已报道的PZA和一系列相关化合物的作用模式，目的是确定协同反应中PMF破坏和反式翻译抑制的相对重要性。这些结果将有可能转化为新的和新颖的先导化合物的开发，这些化合物被设计为与现有的和新的药物协同作用。

 DESCRIPTION (provided by applicant): The need for novel, more efficient and safer drugs capable of addressing the growing issue of multidrug-resistant tuberculosis (MDR-TB) and other antimicrobial resistances call for strategies with the ultimate objective of identifying leads showing favorable physicochemical properties, potency and toxicity. A successful strategy is to build on well-established and first line drugs with poorly understood mechanisms of action or synergy. In this proposal we focus on pyrazinamide (PZA), a drug that is synergistic with nearly all other anti-TB drugs and is included in current anti-TB regimens as a means of reducing the treatment time from nine to six months. However, the mode of action of this drug remains controversial, and no data explains the mechanism behind the powerful synergism between this drug and others. Recent studies have proposed a role in inhibition of trans-translation and/or disruption of bacterial ATP synthesis. Our work with an anti-tubercular in phase 2 clinical trials, SQ-109, and analogs led us to conclude that disruption of proton motive force (PMF), in addition to enzyme inhibition, is important to the efficacy of these compounds. Thus, we hypothesize that disruption of PMF plays a significant role in the synergistic properties of PZA. In this project we propose to dissect the reported modes of action of PZA and a series of related compounds with the goal of determining the relative importance of PMF disruption and trans-translation inhibition in the synergistic response. The results will potentially translate into the development of new and novel lead compounds that are designed to be synergistic with existing and new drugs.