Tideglusib and Its Analogues As Inhibitors of SrtA.

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 (), a drug candidate for myotonic dystrophy, was outstanding in high-throughput screening. A concise synthetic route quickly provided analogues, and the structure-activity relationships for SrtA inhibition have been established from those analogues. Several compounds largely retained the potency and exhibited a better solubility than . Additionally, attenuated virulence-related phenotypes and protected mice against lethal USA300 bacteremia. Our study indicates that and its analogues could be new candidates as SrtA inhibitors with potential in the development of new antivirulence agents.