Tideglusib and Its Analogues As Inhibitors of <i>Staphylococcus aureus</i> SrtA

Abstract

Sortase A (SrtA) anchors surface proteins to the cell wall envelope, and it has attracted increasing interesting as a potential antivirulence target. Several small-molecule inhibitors for SrtA have been developed, but target validation remains largely underexplored. Herein, we report a new class of SrtA inhibitors that supports antivirulence therapy through small-molecule targeting of SrtA. Tideglusib (<b>TD</b>), a drug candidate for myotonic dystrophy, was outstanding in high-throughput screening. A concise synthetic route quickly provided <b>TD</b> analogues, and the structure-activity relationships for SrtA inhibition have been established from those analogues. Several compounds largely retained the <i>in vitro</i> potency and exhibited a better solubility than <b>TD</b>. Additionally, <b>TD</b> attenuated virulence-related phenotypes <i>in vitro</i> and protected mice against lethal <i>S. aureus</i> USA300 bacteremia. Our study indicates that <b>TD</b> and its analogues could be new candidates as SrtA inhibitors with potential in the development of new antivirulence agents.