Anti-virulence drug repurposing using structural systems pharmacology

摘要 对万不得已的抗生素产生抗药性的超级细菌的出现对人类构成了严重威胁 健康，我们正在“与时间赛跑，开发新的抗生素”。迫切需要新的方法来 控制耐药病原体，减少新的耐药微生物的出现。这个 改变安全药物的用途以针对细菌毒力已成为打击毒品的重要战略-- 抗药性病原体。使用结构系统药理学方法，该方法基于已发表的和 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 调节剂(SERM)雷洛昔芬，目前用于预防骨质疏松症和侵袭性乳房 绝经后女性的癌症，以及男性女性乳房发育症的治疗，都会强烈地减弱 秀丽隐杆线虫感染模型中铜绿假单胞菌的毒力。雷洛昔芬预计将 结合铜绿假单胞菌PhzB2，这是生产蓝色素绿色素所必需的 通过吩嗪生物合成途径产生。绿青素对真核细胞有毒性，已被证明 在感染中发挥关键作用，使其成为抗感染药物开发的有吸引力的靶点。这些结果 提示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 治疗铜绿假单胞菌感染。这项建议将在临床前验证雷洛昔芬的有效性。 用小鼠感染模型和严格统计学方法减轻铜绿假单胞菌毒力 分析，并确定针对相同吩嗪的FDA批准的潜在更有效的药物 生物合成途径。该项目的顺利完成将为控制和控制提供一个很有前途的解决方案 抗药性病原体，从而解决了针对药物的新药的重大未得到满足的医疗需求- 抗药性病原体。

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.