Insights into the structure-activity relationship of a type III secretion system inhibitor, aurodox

Aoi Kimishima; Daichi Hagimoto; Masako Honsho; Yoshihiro Watanabe; Masato Iwatsuki; Hayama Tsutsumi; Yuki Inahashi; Kamrun Naher; Kazunari Sakai; Asaomi Kuwae; Akio Abe; Yukihiro Asami

doi:10.1016/j.bmcl.2022.128779

Insights into the structure-activity relationship of a type III secretion system inhibitor, aurodox

Bioorg Med Chem Lett. 2022 Aug 1:69:128779. doi: 10.1016/j.bmcl.2022.128779. Epub 2022 May 8.

Authors

Affiliations

¹ Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan; Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan.
² Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
³ Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan.
⁴ Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan; Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan. Electronic address: yasami@lisci.kitasato-u.ac.jp.

PMID: 35545199
DOI: 10.1016/j.bmcl.2022.128779

Abstract

Aurodox was originally isolated in 1972 as a linear polyketide compound exhibiting antibacterial activity against Gram-positive bacteria. We have since identified aurodox as a specific inhibitor of the bacterial type III secretion system (T3SS) using our original screening system for inhibition of T3SS-mediated hemolysis in enteropathogenic Escherichia coli (EPEC). In this research, we synthesized 15 derivatives of aurodox and evaluated EPEC T3SS inhibitory activity as well as antibacterial activity against EPEC. One of the derivatives was highly selective for T3SS inhibition, equivalent to that of aurodox, but without exhibiting antibacterial activity (69-fold selectivity). This work revealed the structure-activity relationship for the inhibition of T3SS by aurodox and suggests that the target of T3SS is distinct from the target for antibacterial activity.

Keywords: Antibiotics; Aurodox; Bacterial type III secretion system (T3SS); Enteropathogenic Escherichia coli (EPEC); Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology
Aurodox* / pharmacology
Enteropathogenic Escherichia coli*
Escherichia coli Proteins*
Structure-Activity Relationship
Type III Secretion Systems

Substances

Anti-Bacterial Agents
Escherichia coli Proteins
Type III Secretion Systems
Aurodox