Development of Natural Product Inspired Adjuvants to Treat Tolerant Infections

项目摘要 在过去的几十年里，天然产品一直是一种生产性的药物来源，并 代表或启发了已进入市场的大多数抗菌化合物 诊所。这项建议的目标是开发基于海洋的新型抗菌佐剂 天然产物赛诺唑酮B治疗革兰氏阳性骨科关节感染。这些 支架有可能清除生物被膜相关的顽固性感染，基于初步的 体外数据。这些与生物被膜有关的感染对传统抗生素耐药，并代表着 由于高达80%的人类感染涉及生物被膜相关，这是一项重要的临床需求 微生物。很少有小分子被分离出来，它们有可能破坏 生物膜，从而起到清除生物膜相关感染的作用。在此，我们建议开发 一类能够治疗生物被膜相关性感染的化合物 并生成关键数据，以决定是否通过将这些分子推进到 第二阶段临床前研究。

Project Summary Natural products have served as a productive source of drugs over the past decades and have represented, or been the inspiration for, a majority of antimicrobial compounds that have entered the clinic. The goal of this proposal is to develop novel antibacterial adjuvants based on the marine natural product synoxazolidinone B to treat Gram-positive orthopedic joint infections. These scaffolds have the potential to clear biofilm-implicated recalcitrant infections based on preliminary in-vitro data. These biofilm-implicated infections are tolerant to traditional antibiotics and represent a significant clinical need since up to 80% of human infections involve biofilm-associated microorganisms. Few small molecules have been isolated that have the potential to disrupt biofilms, thereby functioning to clear biofilm associated infections. Herein, we propose to develop a class of compounds that is capable to addressing the treatment of biofilm associated infections and generate the key data necessary for a go/no-go decision to advance these molecules toward a Phase II pre-clinical study.