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: 10183396
• 负责人: Yutaka Tagaya
• 金额: $ 20.91万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183396
• 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; 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 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 公众日益面临新发传染病的风险。耐药细菌的流行 病原体正在使目前的抗生素无效，并使新药成为必不可少的 开发用来对抗由这些病原体引起的感染。脂类II是细菌的重要前体 膜生物发生和目前临床上已建立的但未充分利用的抗生素靶点 使用。我们首次根据相互作用确定了小分子Lipid II结合体 防御素，一类天然抗菌肽和脂类II.表征 前景看好的Lipid II结合剂揭示了它独特地与Lipid II结合并具有强大的抗肿瘤活性 分枝杆菌。该提案旨在验证和优化合成Lipid II结合剂作为一种新的类别 抗生素化合物，以对抗由这些难以治疗的细菌引起的病原性感染。