Development of novel penems for drug-resistant tuberculosis

项目总结 世界卫生组织在其2015年的报告中宣布，结核病(TB)导致的死亡人数超过 任何其他感染源。而对药物敏感的结核病的治疗需要联合治疗至少 6个月，治疗耐多药结核病(DR-TB)需要用多种有毒、昂贵的药物治疗 而疗效较差的二线/三线药物最长可达2年。即便如此，只有约50%的DR-TB病例 接受治疗有成功的结果。在最近的一项研究中，12%的接受治疗的耐药结核病病例患上了 在治疗过程中出现额外的耐药性。因此，新的药物和创新的疗法是 迫切需要有效地对抗耐药结核病。 开发新的药物和方案是我们结核病研究中心和我们的 长期的行业合作伙伴，结核病联盟。在过去的十年里，我们的临床前方案识别 该计划确定了7种新的药物组合，其中包含2-3种未经批准用于结核病治疗的药物 随后进入临床试验阶段。结核病联盟资助的第三阶段试验正在进行中(n=2)或正在进行 计划3个方案(n=1)，均包括耐多药结核病患者。然而，仍然有很大的需求 有效的新型口服制剂，用于更安全和更普遍的有效疗法，而不会发生药物与药物的相互作用。 最近对碳青霉烯类美罗培南治疗结核病的临床概念验证在 与阿莫西林/克拉维酸联用。我们已经开发出一系列化学上截然不同的合成材料 青霉烯类抗生素，具有优于现有碳青霉烯类抗生素的全细胞效力，因为它们被优化用于 抑制转肽酶活性的非经典L，D-转肽酶 结核分枝杆菌合成肽多糖的最后一步。我们测定了其中一个的晶体结构 我们的铅青霉(T402)与结核分枝杆菌L，D-转肽酶结合并提出了一种独特的机制 行动的一部分。结构差异是为了提高抗结核分枝杆菌的效力和选择性 并将自发阻力降至最低。该提案描述了一个全面的、里程碑驱动的预案 临床发展计划，主要目标是提供一种新的青霉烯类和新青霉烯类- 包含可用于IND的毒性研究和进一步的临床开发的方案，用于治疗 耐药结核病。

PROJECT SUMMARY In its 2015 report, the World Health Organization declared that tuberculosis (TB) killed more humans than any other infectious agent. While treatment of drug susceptible TB requires combination therapy for at least six months, treatment of multidrug-resistant TB (DR-TB) requires treatment with multiple toxic, expensive and less efficacious second/third line drugs for up to 2 years. Even then, only ~50% of DR-TB cases that receive treatment have successful outcomes. In a recent study, 12% of treated DR-TB cases developed additional drug resistance during treatment. Therefore, new drugs and innovative regimens that are effective against drug-resistant TB are urgently needed. Development of new drugs and regimens is a core mission of our Center for Tuberculosis Research and our longstanding industry partner, the TB Alliance. Over the past decade, our Pre-clinical Regimen Identification Program identified 7 novel drug combinations containing 2-3 drugs unapproved for TB treatment that subsequently advanced to clinical trials. TB Alliance-funded phase 3 trials are underway (n=2) or being planned (n=1) for 3 regimens, all of which include MDR-TB patients. Yet, there remains a great need for potent new, oral agents for safer and more universally active regimens without drug-drug interactions. Clinical proof-of-concept for TB therapy was recently demonstrated for the carbapenem meropenem in combination with amoxicillin/clavulanate. We have developed a series of chemically distinct synthetic penems, with superior whole cell potency over existing carbapenems, owing to their being optimized for inhibition of non-classical L,D-transpeptidases that comprise the predominant transpeptidase activity during the final step of peptidoglycan synthesis in M. tuberculosis. We determined the crystal structure of one of our lead penems (T402) bound to a M. tuberculosis L,D-transpeptidase and proposed a unique mechanism of action. Structural differences were engineered to enhance potency and selectivity against M. tuberculosis and to minimize spontaneous resistance. This proposal describes a comprehensive, milestone-driven pre- clinical development plan with the principal objective of delivering a novel penem and novel penem- containing regimens ready for IND-enabling toxicity studies and further clinical development for treatment of DR-TB.