Development of novel penems for drug-resistant tuberculosis

项目摘要 在2015年的报告中，世界卫生组织宣布，结核病（TB）造成的死亡人数超过 任何其他传染源。虽然药物敏感性结核病的治疗需要至少 六个月，治疗耐多药结核病（DR-TB）需要治疗多种有毒，昂贵的 和有效性较低的二线/三线药物长达2年。即便如此，只有约50%的耐药结核病例 治疗取得了成功的结果。在最近的一项研究中，12%的耐药结核病例 在治疗过程中增加耐药性。因此，新的药物和创新的方案， 有效对抗耐药结核病。 开发新的药物和治疗方案是我们结核病研究中心的核心使命， 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 该项目确定了7种含有2-3种未批准用于结核病治疗的药物的新型药物组合， 随后进入临床试验。TB联盟资助的3期试验正在进行中（n=2）或正在进行中 计划（n=1）用于3种方案，所有方案均包括耐多药结核患者。然而，仍然非常需要 有效的新型口服药物，用于更安全和更普遍的活性方案，无药物相互作用。 结核病治疗的临床概念验证最近被证明是碳青霉烯美罗培南， 与阿莫西林/克拉维酸联合使用。我们开发了一系列化学性质不同的合成 青霉烯类，具有优于现有碳青霉烯类的全细胞效力，这是由于它们被优化用于 抑制非经典的L，D-转肽酶，其包含主要的转肽酶活性， 在M.结核我们确定了一种 我们的铅青霉烯（T402）结合到一个M。结核菌L，D-转肽酶，并提出了独特的机制 的行动。设计结构差异以增强针对M的效力和选择性。结核 并使自发阻力最小化。该提案描述了一个全面的、里程碑式的预 临床开发计划，主要目的是提供一种新的青霉烯和新的青霉烯- 包含可用于IND启动毒性研究和进一步临床开发的治疗方案， 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.