Anti-virulence drug repurposing using structural systems pharmacology

摘要 超级细菌的出现对最后的抗生素产生了抗药性，对人类构成了严重威胁。 我们正在“与时间赛跑，开发新的抗生素”。迫切需要采取新的办法， 控制耐药病原体，减少新的耐药微生物的出现。的 重新利用安全药物以靶向细菌毒力已成为对抗药物滥用的重要策略， 耐药病原体。使用结构系统药理学方法，该方法基于已发表的和 利用公开可用的计算工具和数据库，我们发现选择性雌激素受体 雷洛昔芬是一种目前用于预防骨质疏松症和浸润性乳腺癌的药物， 绝经后妇女的癌症，以及男性乳房发育的治疗， 铜绿假单胞菌在秀丽隐杆线虫感染模型中的毒力雷洛昔芬预计 结合铜绿假单胞菌PhzB2，这是必不可少的蓝色色素绿脓菌素的生产 通过吩嗪生物合成途径产生。绿脓菌素对真核细胞有毒，并且已被证明 在感染中发挥关键作用，使其成为抗感染药物发现的有吸引力的靶点。这些结果 这表明FDA批准的药物雷洛昔芬可能适合作为治疗药物进一步开发 铜绿假单胞菌感染该提案将对雷洛昔芬的有效性进行临床前验证 使用小鼠感染模型和严格的统计学方法， 分析，并确定潜在的更有效的FDA批准的药物，目标相同的吩嗪 生物合成途径该项目的成功实施，将为我国城市道路交通的控制提供一个很有前途的解决方案。 耐药病原体，从而解决了针对耐药病原体的新药的重大未满足的医疗需求， 耐药病原体。

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.