Development of Single Agent Antibiofilm Antibiotics

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剂 天然产物脂氧唑烷酮A用于治疗顽固性革兰氏阳性感染。这些脚手架 有可能清除与生物膜有关的顽固性感染，包括持久性组织 感染，如慢性伤口感染、慢性骨髓炎、慢性鼻窦炎和 心内膜炎。这些与生物膜有关的感染对传统抗生素和 代表着重要的临床需求，因为高达80%的人类感染涉及生物膜- 伴生微生物。很少有小分子被分离出来，它们有可能 不仅破坏生物膜，还起到抗生素的作用，从而起到清除生物膜的作用。 相关感染。我们相信单一药物治疗有显著的优势。 而不是用于治疗这些生长缓慢的耐药感染的辅助疗法。 在此，我们建议开发一类能够解决这种治疗的化合物 并生成关键数据，以便做出通过/不通过决策 将这些分子推进到II期临床前研究。

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 agents based on the marine natural product lipoxazolidinone A to treat recalcitrant Gram-positive infections. These scaffolds have the potential to clear biofilm-implicated recalcitrant infections, including persistent tissue infections such as chronic wound infections, chronic osteomyelitis, chronic rhinosinusitis and endocarditis. 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 not only disrupt biofilms, but also act as an antibiotic – thereby functioning to clear biofilm associated infections. We believe there are significant advantages to a single agent treatment over an adjuvant therapy for the treatment of these slow-growing, antimicrobial tolerant 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.