The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile

Clostridium difficile infections
(CDI), particularly those caused by the BI/NAP1/027 epidemic strains,
are challenging to treat. One method to address this disease is to
prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified
cholic amide m-sulfonic acid, CamSA, as an inhibitor
of spore germination. However, CamSA is inactive against the hypervirulent
strain R20291. To circumvent this problem, a series of cholic acid
amides were synthesized and tested against R20291. The best compound
in the series was the simple phenyl amide analogue which possessed
an IC50 value of 1.8 μM, more than 225 times as potent
as the natural germination inhibitor, chenodeoxycholate. This is the
most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling
analysis demonstrated that increases in hydrophobicity and decreases
in partial charge or polar surface area were correlated with increases
in potency.