Antiviral Library Screening Leads to Discovery of Novel and Potent Anticlostridial Compounds

Abstract

Clostridium difficile (C. difficile) is a major cause of nosocomial infections, often associated with individuals who have gut dysbiosis from previous antibiotic therapies. C. difficile infections have a high recurrence rate and impose significant financial and mortality burdens on the healthcare system. Novel anti-C. difficile drugs are urgently needed to treat and reduce the severity and recurrence of infection. In this study, we screened a library of 618 antiviral drugs to identify a potential candidate for repurposing as novel anti-C. difficile treatments. Following our preliminary screening, we identified 9 novel compounds that inhibit C. difficile at a concentration of 16 {micro}M or lower. Among these, 4 antiviral compounds demonstrated the most potent anti-C. difficile activity against a panel of 15 C. difficile isolates, with minimum inhibitory concentrations (MICs) comparable to the drug of choice, vancomycin. These include rottlerin (MIC50 = 0.25 {micro}g/mL), -mangostin (MIC50 = 1 {micro}g/mL), dryocrassin ABBA (MIC50 = 1 {micro}g/mL), and obefazimod (MIC50 = 4 {micro}g/mL). All exhibited minimal to no activity against representative members of the gut microbiota. Interestingly, -mangostin, a natural xanthone derived from the mangosteen fruit, exhibited strong bactericidal action, clearing a high inoculum of C. difficile in less than an hour. All other drugs exhibited bacteriostatic activity. Given the characteristics of these compounds, they show great promise as novel treatments for CDI.