Intestinal Bile Acids Directly Modulate the Structure and Function of TcdB Toxin

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Mar 11

PMID 32152097

Citations 38

Authors

John Tam

Simoun Icho

Evelyn Utama

Kathleen E Orrell

Rodolfo F Gomez-Biagi

Casey M Theriot

Heather K Kroh

Stacey A Rutherford

D Borden Lacy

Roman A Melnyk

Affiliations

Soon will be listed here.

Abstract

Intestinal bile acids are known to modulate the germination and growth of Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant of disease. 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 in pathogenesis, these findings provide a framework for development of a mechanistic class of antitoxins.

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