Development of novel penems for drug-resistant tuberculosis

治疗耐药结核病的新型青霉烯类药物的开发

• 批准号: 10077824
• 负责人: ERIC L NUERMBERGER
• 金额: $ 75.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-03 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077824
• 关键词: AIDS/HIV problem; Amoxicillin; Anti-Bacterial Agents; Antitubercular Agents; Back; Bacteria; Binding; Biological Assay; Biological Availability; Carbapenems; Cells; Chemicals; Chemistry; Clavulanate; Clinical; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Crystallization; Development; Development Plans; Dose; Drug Interactions; Drug resistance; Drug resistance in tuberculosis; Engineering; Enzyme Inhibition; Exhibits; Extreme drug resistant tuberculosis; Frequencies; Funding; Glycopeptides; Goals; Human; In Vitro; Incidence; Infectious Agent; Kidney; Kinetics; Lead; Legal patent; Libraries; Measures; Meropenem; Mission; Molecular; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Oral; Outcome; Patients; Penicillin-Binding Proteins; Peptidoglycan; Peptidyltransferase; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Physiology; Prodrugs; Program Development; Reaction; Regimen; Reporting; Research; Resistance; Series; Source; Structure; Therapeutic; Toxic effect; Treatment Protocols; Treatment outcome; Tuberculosis; Vertebral column; Work; World Health Organization; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; clinical candidate; clinical development; design; drug metabolism; drug-sensitive; in vivo; industry partner; innovation; lead candidate; lead series; mindfulness; mouse model; novel; novel drug class; novel drug combination; novel therapeutics; phase III trial; pre-clinical; preclinical development; preclinical study; priority pathogen; programs; resistant strain; response; therapy development; transpeptidation; tuberculosis treatment

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.

项目概要 世界卫生组织在 2015 年报告中宣布，死于结核病 (TB) 的人数超过 任何其他传染源。虽然治疗药物敏感结核病需要联合治疗至少 六个月内，治疗耐多药结核病（DR-TB）需要使用多种有毒、昂贵的药物进行治疗 以及效果较差的二线/三线药物长达 2 年。即便如此，只有约 50% 的耐药结核病病例 接受治疗取得成功的结果。在最近的一项研究中，接受治疗的耐药结核病病例中有 12% 发展为耐药结核病 治疗期间额外的耐药性。因此，新药和创新疗法 迫切需要有效对抗耐药结核病的药物。 开发新药和治疗方案是我们结核病研究中心和我们的核心使命 长期行业合作伙伴结核病联盟。在过去的十年里，我们的临床前方案鉴定 计划确定了 7 种新型药物组合，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。结核病联盟资助的第 3 期试验正在进行中 (n=2) 或正在进行中 计划 (n=1) 3 种方案，所有方案均包括耐多药结核病患者。然而，仍然非常需要 有效的新型口服药物，可实现更安全、更普遍的有效治疗方案，且无药物间相互作用。 最近证明了碳青霉烯美罗培南的结核病治疗临床概念验证 与阿莫西林/克拉维酸组合。我们开发了一系列化学性质不同的合成材料 青霉烯类，由于针对现有碳青霉烯类进行了优化，因此具有优于现有碳青霉烯类的全细胞效力 抑制非经典 L,D-转肽酶，其中包含主要转肽酶活性 结核分枝杆菌中肽聚糖合成的最后一步。我们确定了其中之一的晶体结构 我们的先导青霉烯类 (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 的行动。设计结构差异以增强针对结核分枝杆菌的效力和选择性 并尽量减少自发抵抗。该提案描述了一个全面的、里程碑驱动的预 临床开发计划的主要目标是提供一种新型青霉烯类药物和新型青霉烯类药物 包含可用于 IND 毒性研究和进一步临床开发的治疗方案 耐药结核病。