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.

该项目的目的是开发UDEP抗生素，这会导致细菌细胞自消化 通过激活CLPP蛋白酶。这种独特的“激活”机制导致迅速和 抗药性病原体的特殊杀害。 UDEPS也有重要优势 - 杀死 代谢活性和休眠形式的病原体。许多细菌通过 传统的抗生素，甚至通过简单生长就可以长时间生存高浓度 在持久细胞的情况下，慢慢或根本没有。这些存活细胞有助于表型 抗生素耐药性，引起复发性感染，并解释为什么传统抗生素无法 杀死限制获得免疫系统的生物膜。但是，细菌不能 通过关闭或等待抗生素水平在激活CLPP时脱落而逃脱死亡 蛋白酶由紫外线。 UDEPS不仅靶向抗菌病原体，还可以允许 常见的感染将通过较少复发而更快，有效地治疗，而慢性病 感染性心内膜炎，骨髓炎，导管相关的血液感染和假肢 联合感染可以首次用抗生素治愈。结构指导医学 化学计划导致了UDEPS系列的发现，其中许多都具有出色的药物样 与第一代acyldepspepeptides相比。曲线下的区域的重大收益 （AUC），CMAX，半衰期和清除率，同时保持效力。最近 结构性进步使我们能够优先考虑铅状UDEP，3349。此化合物显示 多种感染动物模型的功效，对人类具有高度预测性，包括 败血症，中性大腿，肺炎，以及复杂的生物膜异物模型 在这项研究中，3349将用于基准测试旨在 进一步提高可吸毒性，以生产适合于临时临床前进的铅候选者 发展。这些研究将以四个目的进行：（i）进一步优化后期铅 使用结构和PK指导设计的UDEP； （ii）体外药物分析以最大化 安全性和感染的空心纤维模型将用于指导剂量选择和选择 抗生素伴侣； （iii）在腹膜炎感染模型中的体内效率测定， 中性粒细胞减少性大腿，肺肺炎，植入导管生物膜和心内膜炎； （iv）临床前 开发，使用详细的体内PK/PD剂量，给药间隔和目标成就将支持 辅助研究。有毒动力学研究将支持选择剂量选择，毒理学终点和 符合GLP研究的有毒动力学时间点。这些研究将为风险提供基础 - 在与FDA会面之前的福利评估。