Exploiting new drug targets in extremely resistant M.abscessus by using small molecule Lipid II binders

使用小分子脂质 II 结合剂在极其耐药的脓肿分枝杆菌中开发新的药物靶点

• 批准号: 10378085
• 负责人: Yutaka Tagaya
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378085
• 关键词: Acute; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Biological Assay; Cell Wall; Cell-Mediated Cytolysis; Clinical; Country; Defensins; Development; Emerging Communicable Diseases; Family; Genus Mycobacterium; Goals; Healthcare Systems; Human; In Vitro; Infection; Laboratories; Lead; Lipids; Lung infections; Multi-Drug Resistance; Mutation; Mycobacterium Infections; Mycobacterium abscessus; Nightmare; Nosocomial Infections; Pathogenicity; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prevalence; Program Development; Property; Resistance; Risk; Serum; Structure; Testing; Therapeutic; Time; Toxic effect; Work; alpha-Defensins; analog; antimicrobial peptide; bacterial resistance; base; combat; drug development; drug resistant bacteria; fight against; fighting; improved; in silico; in vivo; in vivo evaluation; lead optimization; membrane biogenesis; multi-drug resistant pathogen; natural antimicrobial; new therapeutic target; non-tuberculosis mycobacteria; novel; novel antibiotic class; novel therapeutics; pathogen; pathogenic bacteria; precursor cell; resistance mechanism; small molecule; small molecule inhibitor; soft tissue

Abstract The public is increasingly at risk to emerging infectious diseases. The prevalence of resistant bacterial pathogens is rendering current antibiotics ineffective, and making it essential that new drugs be developed to fight infections caused by these agents. Lipid II is an essential precursor in bacterial membrane biogenesis and an established, yet underutilized target for antibiotics currently in clinical use. We have for the first time identified small molecule Lipid II binders, based on the interaction between defensins, a family of natural antimicrobial peptides and Lipid II. Characterization of promising Lipid II binders reveals that it uniquely binds to Lipid II and has potent activty against Mycobacteria. This proposal aims to validate and optimize synthetic Lipid II binders as a novel class of antibiotic compounds to combat pathogenic infections caused by these hard-to-treat bacteria.

摘要