Development of ureadepsipetides for drug-resistant infections

这个项目的目标是开发UDEP抗生素，这种抗生素能使细菌细胞自我消化 通过激活ClpP蛋白水解酶。这种独特的“激活”机制导致快速和 对抗药性病原体的特殊杀灭。UDEP还有一个重要的优势--杀戮 新陈代谢活跃和休眠状态的病原体。许多细菌通过 传统抗生素，即使通过简单地生长在高浓度下长时间存活 在宿存细胞的情况下，缓慢或根本不存在。这些存活的细胞对表型有贡献 抗生素耐药性，导致反复感染，并解释为什么传统抗生素无法 杀死生物膜，它们限制了免疫系统的访问。然而，细菌不能 通过关闭或等待ClpP激活后抗生素水平下降来逃脱死亡 UDEP的蛋白酶。UDEP不仅针对抗菌素耐药病原体，还可能允许 常见感染得到更快、更有效的治疗，复发更少，而慢性感染 感染如心内膜炎、骨髓炎、导管相关的血流感染和假体 关节感染可以第一次用抗生素治愈。一种引导药用的结构 化学程序导致了UDEP系列的发现，其中许多具有优越的类药物 与第一代酰基多肽的性质比较。曲线下面积的主要增长 在保持效力的同时，达到了(AUC)、Cmax、半衰期和清除期。最近 结构性进展使我们能够优先考虑类似铅的UDEP，3349。该化合物显示 对人类具有高度预测性的多种动物感染模型的疗效，包括 败血症、中性粒细胞减少的大腿、肺炎和复杂的生物膜异物模型 感染。在这项研究中，3349将被用来对最近的导联子库进行基准测试，旨在 进一步提高可药性，生产出适合进入临床前阶段的领先候选药物 发展。这些研究将以四个目标进行：(I)进一步优化后期领导 使用结构和PK指导设计的UDEPs；(Ii)体外药理图谱 安全性，中空纤维感染模型将用于指导剂量选择和 抗生素伙伴；(Iii)腹膜炎败血症感染模型的体内疗效测定， 中性粒细胞减少的大腿、肺部肺炎、植入的导管生物膜和心内膜炎；(4)临床前 开发，使用详细的体内PK/PD剂量、给药间隔和目标实现将支持 支持IND的研究。毒物动力学研究将支持剂量选择、毒理学终点和 GLP依从性研究的毒代动力学时间点。这些研究将为风险提供基础- 在与FDA会面之前进行福利评估。

The goal of this project is to develop UDEP antibiotics, which cause bacterial cells to self-digest through activation of the ClpP protease. This unique “activating” mechanism causes rapid and exceptional killing of drug resistant pathogens. UDEPs also have an important advantage – killing of both metabolically active and dormant forms of pathogens. Many bacteria evade killing by traditional antibiotics, even surviving high concentrations for prolonged periods by simply growing slowly or not at all, in the case of persister cells. These surviving cells contribute to phenotypic antibiotic resistance, cause recurrent infections, and explain why traditional antibiotics are unable to kill biofilms, which have restricted access to the immune system. However, bacteria cannot escape death by shutting down or waiting until antibiotic levels drop upon activation of ClpP proteases by UDEPs. UDEPs not only target antimicrobial resistant pathogens, but may also allow common infections to be treated more quickly and effectively with less recurrence, while chronic infections like endocarditis, osteomyelitis, catheter-related bloodstream infections and prosthetic joint infections could be cured with antibiotics for the first time. A structure guided medicinal chemistry program led to the discovery of the UDEPs series, many of which have superior drug-like properties compared to the first generation acyldepsipeptides. Major gains in area under the curve (AUC), Cmax, half-life, and clearance have been achieved, while maintaining potency. A recent structural advance has enabled us to prioritize a lead-like UDEP, 3349. This compound displays efficacy in multiple animal models of infection which are highly predictive for humans, including septicemia, neutropenic thigh, pneumonia, and in a complicated model of biofilm foreign body infection. In this study, 3349 will be used to benchmark a sub-library of late leads designed to further improve druggability to produce a lead candidate suitable to be advanced into pre-clinical development. These studies will be performed in four aims: (i) Further optimization of late lead UDEPs using structure and PK guided design; (ii) in vitro pharmacological profiling to maximize safety, and hollow-fiber models of infection will be used to guide dose selections and the choice of antibiotic partners; (iii) in vivo efficacy determination in infection models of peritonitis septicemia, neutropenic thigh, lung pneumonia, implanted catheter biofilms and endocarditis; (iv) Preclinical development, using detailed in vivo PK/PD dose, dosing interval and target attainment will support IND-enabling studies. Toxicokinetic studies will support dose selection, toxicology endpoints and toxicokinetic time points for GLP-compliant studies. These studies will provide the basis for a risk- benefit assessment prior to meeting with the FDA.