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

该项目的目标是开发一种新型的尿素脱肽(UDEP)抗生素来治疗假肢关节。 感染(PJI)。UDEP通过激活ClpP蛋白酶杀死细菌，导致细胞自我消化。这个独一无二的 激活机制允许UDEP杀死生物膜和不生长的持久细胞，这些细胞普遍存在于PJI和PJI中 解释为什么目前的抗生素在很大程度上无效。目前的治疗方法包括几周到几个月的抗生素 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而采取的干预措施，改善了患者护理。产后肺炎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UDEPs对这些病原体具有很强的活性，包括多种药物。 耐药菌株。我们UDEP药物化学项目的最新进展产生了一种新的化合物，它已经 与第一代UDEP相比，安全性、溶解性和骨穿透性都有所改善。初步研究发现， 该化合物在PJI的K型钢丝股骨髓管植入模型中有效，已知PJI很难 请客。在这个项目中，我们将评估该化合物是否为可接受的PJI临床前候选药物，方法是在 一系列体外和体内研究都集中在这一适应症上。具体地说，目标是1)扩大化合物的规模；2) 测定PJI主要病原菌的微生物和生物膜杀灭效果；3)测定 复方对小鼠和兔PJI模型的疗效观察。

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.