Development of ureadepsipetides for drug-resistant infections

治疗耐药感染的脲肽肽的开发

• 批准号: 10063811
• 负责人: Michael LaFleur
• 金额: $ 120.96万
• 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/10063811
• 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; 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，这种抗生素能使细菌细胞自我消化 通过激活ClpP蛋白酶。这种独特的“激活”机制导致快速和 对耐药病原体的异常杀灭。民主行动党还有一个重要的优势， 代谢活跃和休眠形式的病原体。许多细菌通过以下方式逃避杀灭： 传统的抗生素，即使在高浓度下长时间生存， 对于持留细胞来说，是缓慢的还是根本没有。这些存活的细胞有助于表型 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 来杀死生物膜，生物膜限制了免疫系统的进入。然而，细菌不能 通过关闭或等待抗生素水平在ClpP激活后下降来逃避死亡 UDEPs的蛋白酶。UDEP不仅针对耐药性病原体， 常见感染得到更快速有效的治疗，复发率更低，而慢性感染 感染，如心内膜炎、骨髓炎、导管相关血流感染和假体 关节感染首次可以用抗生素治愈。一种结构导向药物， 一个化学项目导致了UDEP系列的发现，其中许多具有上级药物样活性。 与第一代酰基缩酚肽相比，曲线下面积大幅增加 (AUC)Cmax、半衰期和清除率，同时保持效力。最近的一 结构进步使我们能够优先考虑铅样UDEP，3349。这种化合物显示 在多种动物感染模型中的疗效，这些模型对人类具有高度预测性，包括 败血症，大腿贫血，肺炎，以及生物膜异物的复杂模型 感染在本研究中，3349将用于对晚期潜在客户的子库进行基准测试， 进一步提高药物的可药性，以产生适合于进入临床前的先导候选物， 发展这些研究将在四个目标下进行：（i）进一步优化晚期电极导线 使用结构和PK指导设计的UDEP;（ii）体外药理学特征分析，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 抗生素伴侣;（iii）腹膜炎败血症感染模型中的体内功效测定， 大腿贫血、肺炎、植入导管生物膜和心内膜炎;（iv）临床前 使用详细的体内PK/PD剂量、给药间隔和目标达到情况，将支持 国家研究开发扶持性研究。毒代动力学研究将支持剂量选择、毒理学终点和 GLP合规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会面之前进行利益评估。