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

基本信息

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
项目类别：
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

项目摘要

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.

该项目的目标是开发一类新型尿素缩肽（UDEP）抗生素来治疗假体关节感染（PJI）。 UDEP 通过激活 ClpP 蛋白酶杀死细菌，导致细胞自我消化。这种独特的激活机制允许 UDEP 杀死生物膜和非生长的持续细胞，这些细胞在 PJI 和解释为什么目前的抗生素基本上无效。目前的疗法需要使用数周至数月的抗生素治疗、清创手术和医疗设备更换。 UDEP 有可能最大限度地减少手术 PJI 的干预措施并改善患者护理。 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以及 UDEP 对这些病原体（包括多种药物）具有有效活性耐药菌株。我们的 UDEP 医学化学项目最近取得了进展，产生了一种新化合物，该化合物已与第一代 UDEP 相比，提高了安全性、溶解度和骨渗透性。初步研究发现该化合物在 PJI 的克氏针股骨髓管植入模型中有效，众所周知，该模型很难对待。在这个项目中，我们将通过在一个实验室中进行测试来评估该化合物是否是 PJI 可接受的临床前候选药物。一系列体外和体内研究都集中在这一适应症上。具体来说，目标是 1) 扩大化合物规模； 2）确定对从 PJI 中分离出的主要病原体的微生物和生物膜杀灭效果； 3) 确定该化合物在 PJI 小鼠和兔模型中的功效。