Anti-virulence drug repurposing using structural systems pharmacology

利用结构系统药理学重新利用抗毒药物

• 批准号: 9204993
• 负责人: Lei Xie
• 金额: $ 32.84万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204993
• 关键词: Address; Anabolism; Animals; Anti-Infective Agents; Antibiotics; Attenuated; Bacteria; Binding; Caenorhabditis elegans; Chemicals; Clinical Pathways; Clinical Trials; Collaborations; Databases; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Eukaryotic Cell; Experimental Designs; FDA approved; Genomics; Health; Human; In Vitro; Infection; Lead; Ligands; Medical; Metabolic; Methods; Microbe; Modeling; Molecular; Multi-Drug Resistance; Mus; New Jersey; Osteoporosis prevention; Pathway interactions; Peritonitis; Pharmaceutical Preparations; Pharmacology; Phenazines; Phenotype; Pigments; Play; Pneumonia; Postmenopause; Process; Production; Property; Proteins; Proteome; Pseudomonas aeruginosa; Publishing; Pyocyanine; Quantitative Structure-Activity Relationship; Race; Raloxifene; Resistance; Resort; Safety; Selective Estrogen Receptor Modulators; Statistical Data Interpretation; Structure; Superbug; Survival Rate; System; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Translational Research; Treatment Failure; Virulence; Woman; abstracting; analog; base; combat; computerized tools; cost; disease phenotype; drug development; drug discovery; functional genomics; genome-wide; genomic data; innovation; malignant breast neoplasm; medical schools; men; mouse model; novel; novel strategies; novel therapeutics; pathogen; pre-clinical; pressure; response; structural genomics; success

Abstract The emergence of superbugs that are resistant to the last-resort antibiotics poses a serious threat to human health, and we are in a “race against time to develop new antibiotics.” New approaches are urgently needed to control drug-resistant pathogens, and to reduce the emergence of new drug-resistant microbes. The repurposing of safe drugs to target bacterial virulence has emerged as an important strategy to combat drug- resistant pathogens. Using a structural systems pharmacology approach that is based on published and publically-available computational tools and databases, we discovered that the selective estrogen receptor modulator (SERM) raloxifene, a drug currently used in the prevention of osteoporosis and invasive breast cancer in post-menopausal women, as well as the treatment of gynaecomastia in men, strongly attenuates Pseudomonas aeruginosa virulence in a Caenorhabditis elegans model of infection. Raloxifene is predicted to bind Pseudomonas aeruginosa PhzB2, which is essential for the production of the blue pigment pyocyanin produced via the phenazine biosynthesis pathway. Pyocyanin is toxic to eukaryotic cells and has been shown to play a key role in infection, making it an attractive target for anti-infective drug discovery. These results suggest that the FDA-approved drug raloxifene may be suitable for further development as a therapeutic agent for Pseudomonas aeruginosa infection. This proposal will pre-clinically validate the effectiveness of raloxifene at attenuating Pseudomonas aeruginosa virulence using mouse models of infection and rigorous statistical analysis, and identify potentially more effective FDA-approved drugs that target the same phenazine biosynthesis pathway. The successful completion of this project will provide a promising solution to controlling drug-resistant pathogens, thereby addressing a significant unmet medical need for new drugs against drug- resistant pathogens.

抽象的 抗性抗生素具有抗药性的超级细菌的出现对人类具有严重威胁 健康，我们正在“与开发新抗生素的时间竞争”。迫切需要新的方法 控制耐药的病原体，并减少耐药微生物的出现。 将安全药物重新利用为靶向细菌病毒已成为对抗药物的重要策略 抗性病原体。使用基于发布的结构系统药理学方法和 公共可用的计算工具和数据库，我们发现选择性雌激素接收器 调节剂（SERM）Raloxifene，一种目前用于预防骨质疏松和侵入性乳房的药物 绝经后妇女的癌症，以及男性的妇科治疗，强烈减弱 秀丽隐杆线虫感染模型中的铜绿假单胞菌病毒。雷洛昔芬预计 结合铜绿假单胞菌PHZB2，这对于生产蓝色色素蛋白蛋白至关重要 通过苯嗪生物合成途径产生。化脓性对真核细胞有毒，已显示 在感染中发挥关键作用，使其成为抗感染药物发现的吸引力。这些结果 建议FDA批准的药物ral氧烯可能适合作为治疗剂的进一步发育 用于铜绿假单胞菌感染。该提案将在链式链接情况下验证雷昔芬的有效性 使用小鼠感染和严格统计的小鼠模型减轻铜绿假单胞菌病毒的假单胞菌病毒 分析，并识别靶向同一苯胺的可能更有效的FDA批准药物 生物合成途径。该项目的成功完成将为控制提供有望的解决方案 耐药的病原体，从而解决了对药物的新药物的巨大医疗需求 - 抗性病原体。