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 (TD), a drug candidate for myotonic dystrophy, was outstanding in high-throughput
screening. A concise synthetic route quickly provided TD analogues, and the structure–activity relationships for SrtA
inhibition have been established from those analogues. Several compounds
largely retained the in vitro potency and exhibited
a better solubility than TD. Additionally, TD attenuated virulence-related phenotypes in vitro and protected mice against lethal S. aureus USA300
bacteremia. Our study indicates that TD and its analogues
could be new candidates as SrtA inhibitors with potential in the development
of new antivirulence agents.
Covalent sortase A inhibitor ML346 prevents Galleria mellonella from Staphylococcus aureus infection by interfering in the transpeptidation activity of sortase A for anchoring surface proteins into staphylococci envelope.
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