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

揭示吡嗪酰胺与其他抗结核药物协同作用的起源

• 批准号: 8952987
• 负责人: DEAN C CRICK
• 金额: $ 23.06万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952987
• 关键词: ATP Synthesis Pathway; Acids; Address; Affect; Amidohydrolases; Antimicrobial Resistance; Antitubercular Agents; Bacteria; Behavior; Biological Assay; Chemicals; Child; Data; Development; Drug Interactions; Drug effect disorder; Drug resistance; Drug usage; Drug-sensitive; Enzyme Inhibition; Exhibits; Funding; Future; Goals; Incidence; Lead; Maps; Membrane; Methods; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Property; Proton-Motive Force; Pyrazinamide; Pyrazinamide resistance; Regimen; Relative (related person); Reporting; Research; Resistance; Role; Series; Starvation; Stimulus; Testing; Time; Toxic effect; Translating; Translations; Tuberculosis; Work; amidase; analog; base; clinically relevant; design; in vitro activity; inhibitor/antagonist; mycobacterial; novel; novel strategies; public health relevance; pyrazinoic acid; resistant strain; response; synergism; tuberculosis drugs; tuberculosis treatment; weapons

 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.

 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、更多、更安全的药物，因此需要采取策略，最终目标是识别具有良好理化性质的有效先导化合物一个成功的策略是建立在作用或协同作用机制知之甚少的成熟一线药物的基础上。 （PZA），一种与几乎所有其他抗结核药物具有协同作用的药物，并被纳入当前的抗结核治疗方案中，作为将治疗时间从九个月缩短至六个月的一种手段。但是，该药物的作用方式仍然存在。有争议，并且没有数据解释该药物与其他药物之间的强大协同作用背后的机制，表明我们在 2 期临床中的抗结核药物具有抑制反式翻译和/或破坏细菌 ATP 合成的作用。试验， SQ-109 和类似物使我们得出结论，除了酶抑制之外，质子动力 (PMF) 的破坏对于这些化合物的功效也很重要。因此，我们发现 PMF 的破坏在协同作用中发挥着重要作用。在这个项目中我们。 提议剖析已报道的 PZA 和一系列相关化合物的作用模式，目的是确定 PMF 破坏和反式翻译抑制在协同反应中的相对重要性，结果将有可能转化为新的先导化合物的开发。旨在与现有药物和新药物产生协同作用的化合物。