Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid.
To cause disease, Clostridium difficile spores must germinate in the host gastrointestinal tract. Germination is initiated upon exposure to glycine and certain bile acids, e.g., taurocholate. Chenodeoxycholate, another bile acid, inhibits taurocholate-mediated germination. By applying Michaelis-Menten kinetic analysis to C. difficile spore germination, we found that chenodeoxycholate is a competitive inhibitor of taurocholate-mediated germination and appears to interact with the spores with greater apparent affinity than does taurocholate. We also report that several analogs of chenodeoxycholate are even more effective inhibitors. Some of these compounds resist 7α-dehydroxylation by Clostridium scindens, a core member of the normal human colonic microbiota, suggesting that they are more stable than chenodeoxycholate in the colonic environment.
Sorg
Joseph A
JA
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Sonenshein
Abraham L
AL
D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development*; D013171:Spores, Bacterial / Q000187:drug effects* / Q000254:growth & development*; D013656:Taurocholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D013656:Taurocholic Acid