A New Approach to Treat Prosthetic Joint Infections with a ClpP Activating Antibiotic

使用 ClpP 激活抗生素治疗假体关节感染的新方法

• 批准号: 10576404
• 负责人: Michael LaFleur
• 金额: $ 99.51万
• 依托单位: ARIETIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576404
• 关键词: 3D Print; Acne; Amputation; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Bacteremia; Bacteria; Biological; Biological Assay; Catheters; Cefazolin; Cell Wall; Cells; Chemistry; Coagulase; Collaborations; Combined Antibiotics; Data; Debridement; Depsipeptides; Development; Devices; Drug Combinations; Drug Kinetics; Enrollment; Enterococcus faecalis; Excision; Failure; Femur; Generations; Goals; Healthcare Systems; Human; Immune; Implant; In Vitro; Infection; Joint Prosthesis; Joints; Linezolid; Medical; Medical Device; Microbial Biofilms; Microbiology; Modeling; Multi-Drug Resistance; Mus; Nafcillin; Nutritional; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Patient Care; Patient-Focused Outcomes; Patients; Penetration; Peptide Hydrolases; Periprosthetic joint infection; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phosphoric Monoester Hydrolases; Physicians; Physiological; Placebos; Process; Prodrugs; Prosthesis; Proteins; Relapse; Replacement Arthroplasty; Resistance development; Rifampin; Role; Route; Safety; Scientist; Series; Solubility; Specialist; Staphylococcus aureus; Staphylococcus epidermidis; Structure; Surgeon; Teflon; Testing; Thigh structure; Titanium; Translations; United States; Urea; Vancomycin; access restrictions; antibiotic tolerance; bone; cell growth; design; drug resistance development; drug testing; economic impact; efficacy evaluation; hip replacement arthroplasty; implant material; improved; improved outcome; in vitro testing; in vivo; knee replacement arthroplasty; methicillin resistant Staphylococcus aureus; mortality; mortality risk; mouse model; novel strategies; pathogen; phosphate ester; pre-clinical; prevent; programs; resistance frequency; resistant strain; scale up; standard of care; subcutaneous; tibia; trial design

The goal of this project is to develop a new class of urea-depsipeptide (UDEP) antibiotics to treat prosthetic joint infections (PJI). UDEPs kill bacteria through activation of the ClpP protease, causing cells to self-digest. This unique activating mechanism allows UDEPs to kill biofilms and non-growing persister cells, which are prevalent in PJI and explain why current antibiotics are largely ineffective. Current therapies involve weeks to months of antibiotic treatment, debridement surgeries, and medical device replacement. UDEPs have the potential to minimize surgical interventions due to PJI and improve patient care. PJI are primarily caused by the Gram-positive pathogens Staphylococcus aureus and epidermidis and the UDEPs are potently active against these pathogens, including multi-drug resistant strains. A recent advance in our UDEP medical chemistry program yielded a new compound which has improved safety, solubility, and bone penetration compared to first generation UDEPs. A preliminary study found that the compound was effective in a K-wire femur medullary canal implant model of PJI, which is known to be difficult to treat. In this project, we will evaluate if the compound is an acceptable pre-clinical candidate for PJI by testing it in a series of in vitro and in vivo studies focused on this indication. Specifically, the aims are to 1) scale up the compound; 2) determine the microbiological and biofilm killing effect against the main pathogens isolated from PJI; and 3) determine the efficacy of the compound in mouse and rabbit models of PJI.

本项目的目标是开发一类新的用于治疗人工关节的脲缩酚肽（UDEP）抗生素 感染（PJI）。UDEP通过激活ClpP蛋白酶杀死细菌，导致细胞自我消化。这种独特 激活机制允许UDEP杀死生物膜和非生长的持续细胞，这在PJI中普遍存在， 解释为什么目前的抗生素在很大程度上无效。目前的治疗方法涉及数周至数月的抗生素 治疗、清创手术和医疗器械更换。UDEP有可能最大限度地减少外科手术 由于PJI的干预和改善病人的护理。PJI主要由革兰氏阳性病原体引起 金黄色葡萄球菌和表皮葡萄球菌，UDEP对这些病原体具有强效活性，包括多药耐药性。 耐药菌株我们UDEP医学化学计划的最新进展产生了一种新化合物， 与第一代UDEP相比，安全性、溶解性和骨渗透性得到改善。一项初步研究发现， 该化合物在PJI的克氏针股骨髓管植入物模型中是有效的，已知PJI难以 请客在这个项目中，我们将通过在一个实验室中测试该化合物来评估该化合物是否是PJI可接受的临床前候选物。 一系列体外和体内研究集中于该适应症。具体而言，目标是1）扩大化合物; 2） 确定对从PJI分离的主要病原体的微生物和生物膜杀灭效果;以及3）确定 该化合物在小鼠和兔PJI模型中的功效。