Development of Single Agent Antibiofilm Antibiotics

单剂抗生物膜抗生素的研制

• 批准号: 10189520
• 负责人: Joshua G. Pierce
• 金额: $ 28.92万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189520
• 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 在过去的几十年里，天然产品一直是药物的生产来源， 代表了大多数已进入的抗菌化合物，或者是其灵感来源 诊所本提案的目标是开发基于海洋的新型抗菌剂 天然产物lipoxazolidinone A治疗难治性革兰氏阳性感染。这些支架 有可能清除生物膜相关的寄生虫感染，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 心内膜炎这些涉及生物膜的感染对传统抗生素具有耐受性， 因为高达80%的人类感染涉及生物膜， 相关微生物很少有小分子被分离出来， 不仅破坏生物膜，而且还作为抗生素-从而起到清除生物膜的作用 相关感染。我们相信单药治疗有显著的优势 而不是辅助疗法来治疗这些生长缓慢、耐抗生素的感染。 在此，我们建议开发一类能够解决治疗问题的化合物， 生物膜相关的感染，并生成进行/不进行决定所需的关键数据， 将这些分子推向II期临床前研究。