Intestinal bile acids directly modulate the structure and function ofC. difficileTcdB toxin

Abstract

Intestinal bile acids are known to modulate the germination and growth ofClostridioides difficile. Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant ofC. difficiledisease. We show that individual primary and secondary bile acids reversibly bind and inhibit TcdB to varying degrees through a mechanism that requires the combined oligopeptide repeats region to which no function has previously been ascribed. We find that bile acids induce TcdB into a compact “balled up” conformation that is no longer able to bind cell surface receptors. Lastly, through a high-throughput screen designed to identify bile acid mimetics we uncovered nonsteroidal small molecule scaffolds that bind and inhibit TcdB through a bile acid-like mechanism. In addition to suggesting a role for bile acids inC. difficilepathogenesis, these findings provide a framework for development of a mechanistic class ofC. difficileantitoxins.