Development of ureadepsipetides for drug-resistant infections

治疗耐药感染的脲肽肽的开发

• 批准号: 10308010
• 负责人: Michael LaFleur
• 金额: $ 120.09万
• 依托单位: ARIETIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-17 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308010
• 关键词: Affinity; Animal Model; Antibiotic Resistance; Antibiotics; Area Under Curve; Bacteria; Benchmarking; Binding Proteins; Biological Assay; Biophysics; Canis familiaris; Catheter-related bloodstream infection; Catheters; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinic; Clinical Paths; Combined Antibiotics; Communicable Diseases; Depsipeptides; Development; Dose; Drops; Drug Targeting; Drug resistance; Endocarditis; Enterococcus faecalis; Enzyme Activation; Fiber; Foreign Bodies; Generations; Goals; Half-Life; Hepatocyte; Human; Immune system; Implant; In Vitro; Infection; Joint Prosthesis; Lead; Libraries; Lung; Medicine; Metabolic; Microbial Biofilms; Microbiology; Mitochondria; Modeling; Monitor; Mus; Osteomyelitis; Peptide Hydrolases; Peritonitis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Pneumonia; Process; Prodrugs; Property; Proximal Kidney Tubules; Rattus; Recurrence; Research Personnel; Resistance; Resistance development; Risk-Benefit Assessment; Safety; Septicemia; Series; Solubility; Streptococcus pneumoniae; Structure; Technology; Testing; Thigh structure; Time; Toxicokinetics; Toxicology; Urea; Validation; Vancomycin Resistance; Vancomycin resistant enterococcus; Wolves; Work; Zoran; analog; antimicrobial resistant pathogen; base; chronic infection; combat; cytotoxicity; design; drug development; drug resistant pathogen; improved; in vitro testing; in vivo; in vivo Model; joint infection; lead candidate; meetings; methicillin resistant Staphylococcus aureus; novel; novel antibiotic class; pathogen; pharmacokinetics and pharmacodynamics; preclinical development; prevent; programs; recurrent infection; screening; simulation

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.

该项目的目标是开发 UDEP 抗生素，使细菌细胞自我消化 通过激活 ClpP 蛋白酶，这种独特的“激活”机制会导致快速且有效的结果。 UDEP 对耐药病原体的出色杀灭还有一个重要优势——杀灭。 代谢活跃和休眠形式的病原体许多细菌都逃避杀灭。 传统抗生素，甚至通过简单的生长就能在高浓度下长时间存活 对于持久细胞来说，这些存活的细胞会缓慢地或根本不产生表型。 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，生物膜限制了免疫系统的进入，但细菌却不能。 通过关闭或等待 ClpP 激活后抗生素水平下降来逃脱死亡 UDEP 产生的蛋白酶不仅针对抗菌药物耐药病原体，而且还可能允许 常见感染可以得到更快、更有效的治疗，并且复发率更低，而慢性感染 心内膜炎、骨髓炎、导管相关血流感染和假体感染等感染 首次通过结构引导药物治愈关节感染。 化学项目导致​​了UDEPs系列的发现，其中许多具有优异的类药性 与第一代酰基缩肽相比，曲线下面积显着增加。 (AUC)、Cmax、半衰期和清除率均已达到，同时保持了近期的效力。 结构的进步使我们能够优先考虑类先导 UDEP，3349。该化合物显示 在多种动物感染模型中的疗效对人类具有高度预测性，包括 败血症、中性粒细胞减少性大腿、肺炎以及生物膜异物的复杂模型 在本研究中，3349 将用于对旨在检测晚期线索的子库进行基准测试。 进一步提高成药性，生产适合进入临床前阶段的先导候选药物 这些研究将围绕四个目标进行：(i) 进一步优化后期领先优势。 使用结构和 PK 指导设计的 UDEP；(ii) 体外药理学分析以最大化 安全性和中空纤维感染模型将用于指导剂量选择和药物选择 (iii) 腹膜炎败血症感染模型的体内功效测定， 大腿中性粒细胞减少症、肺部肺炎、植入导管生物膜和心内膜炎； 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 IND 毒代动力学研究将支持剂量选择、毒理学终点和 这些研究将为符合 GLP 标准的毒代动力学时间点研究提供基础。 在与 FDA 会面之前进行效益评估。