Anti-virulence drug repurposing using structural systems pharmacology

点击翻译按钮获取中文摘要

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.