Prospects for flavonoid and related phytochemicals as nature‐inspired treatments for C lostridium difficile infection

Aims There is a need for novel treatments for C lostridium difficile infection ( CDI ). Antibacterial flavonoids are part of a large family of polyphenol phytochemicals with a long history of use in ethnomedicine, but are unexamined against Cl .  difficile . We explored their anti‐difficile properties. Methods and Results Anti‐difficile activities were determined for several naturally occurring flavonoids, olympicin A and synthetic 4‐chromanone and chalcone analogues. With the exception of olympicin A, most naturally occurring phytochemicals tested were poorly active. Diversified synthetic flavonoids resembling olympicin A retained anti‐difficile activity, suggesting olympicin A could act as a pharmacophore to obtain novel agents. They also demonstrated concentration‐dependent killing of logarithmic and stationary phase cultures and reduced sporulation and toxin production. Olympicin A and some synthetic flavonoids dissipated the bacterial transmembrane potential. Interestingly, mutants could only be selected with the analogue 207 at a frequency of 10 −9 . Conclusions Based on the potent anti‐difficile properties of olympicin A and modified flavonoids, further exploration of this class of phytochemicals is warranted. Significance and Impact of the Study C lostridium difficile infection is a major problem in developed countries. These studies point to there being an avenue for optimizing plant‐derived flavonoids, and related antibacterial phytochemicals, as nature‐inspired approaches to treat CDI .