Inhibition of selenoprotein synthesis is not the mechanism by which auranofin inhibits growth of Clostridioides difficile

Abstract

AbstractClostridioides difficile infections (CDIs) are responsible for a significant number of antibiotic-associated diarrheal cases. The standard-of-care antibiotics for C. difficile are limited to fidaxomicin and vancomycin, with the recently obsolete metronidazole recommended if both are unavailable. No new antimicrobials have been approved for CDI since fidaxomicin in 2011, despite varying rates of treatment failure among all standard-of-care drugs. Drug repurposing is a rational strategy to generate new antimicrobials out of existing therapeutics approved for other indications. Auranofin is a gold-containing anti-rheumatic drug with antimicrobial activity against C. difficile and other microbes. In a previous report, our group hypothesized that inhibition of selenoprotein biosynthesis was auranofin’s primary mechanism of action against C. difficile. However, in this study, we discovered that C. difficile mutants lacking selenoproteins are still just as sensitive to auranofin as their respective wild-type strains. Moreover, we found that selenite supplementation dampens the activity of auranofin against C. difficile regardless of the presence of selenoproteins, suggesting that selenite’s neutralization of auranofin is not because of compensation for a chemically induced selenium deficiency. Our results clarify the findings of our original study and may aid drug repurposing efforts in discovering the compound’s true mechanism of action against C. difficile.