Development of Single Agent Antibiofilm Antibiotics

单剂抗生物膜抗生素的开发

• 批准号: 10081566
• 负责人: Joshua G. Pierce
• 金额: $ 29.83万
• 依托单位: SYNOXA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-11 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081566
• 关键词: Address; Adjuvant Therapy; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Infections; Binding; Biological; Biological Assay; Breathing; Budgets; Cells; Chemicals; Chronic; Clinic; Clinical; Clinical Treatment; Collaborations; Data; Development; Diagnosis; Dose; Drug resistance; Endocarditis; Family; Funding; Future; Goals; Gram-Positive Bacterial Infections; Grant; Hand; Human; In Vitro; Infection; Investigational New Drug Application; Joints; Lead; Libraries; Microbial Biofilms; Modeling; Monitor; Natural Products; Operative Surgical Procedures; Orthopedics; Osteomyelitis; Oxazolidinones; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Preparation; Process; Property; Science; Site; Solubility; Source; Staphylococcus aureus; Testing; Therapeutic Agents; Tissues; Toxic effect; Waxes; Work; Wound Infection; analog; antimicrobial; antimicrobial tolerance; base; chronic rhinosinusitis; chronic wound; commercialization; drug development; high throughput screening; improved; in vitro Model; in vivo; marine natural product; microorganism; mouse model; novel; novel therapeutics; overtreatment; pathogen; preclinical study; prevent; scaffold; screening; small molecule; standard of care

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.

项目摘要 在过去的几十年中，天然产品一直是有效的药物来源 代表或是大多数进入的抗菌化合物的灵感 诊所。该提议的目的是开发基于海洋的新型抗菌剂 天然产物Lipoxazolidinone A治疗顽固革兰氏阳性感染。这些脚手架 有可能清除生物膜刺激的顽固感染，包括持续组织 诸如慢性伤口感染，慢性骨髓炎，慢性鼻炎和 心内膜炎。这些生物膜刺激感染对传统抗生素和 代表着巨大的临床需求，因为多达80％的人类感染涉及生物膜 相关的微生物。很少有小分子分离出来 不仅破坏了生物膜，而且还充当抗生素 - 从而起作用可清除生物膜 相关感染。我们认为，单个代理商治疗有很大的优势 通过可调节的治疗来治疗这些缓慢增长的抗菌耐受性感染。 本文中，我们建议开发能够解决治疗的一类化合物 与生物膜相关感染的作品，并生成进行/不进行决定所必需的关键数据 将这些分子推向II期临床前研究。