RESUMO
The alarming global rise in fatalities from multidrug-resistant Staphylococcus aureus (S. aureus) infections has underscored a need to develop new therapies to address this epidemic. Chemoproteomics is valuable in identifying targets for new drugs in different human diseases including bacterial infections. Targeting functional cysteines is particularly attractive, as they serve critical catalytic functions that enable bacterial survival. Here, we report an indole-based quinone epoxide scaffold with a unique boat-like conformation that allows steric control in modulating thiol reactivity. We extensively characterize a lead compound (4a), which potently inhibits clinically derived vancomycin-resistant S. aureus. Leveraging diverse chemoproteomic platforms, we identify and biochemically validate important transcriptional factors as potent targets of 4a. Interestingly, each identified transcriptional factor has a conserved catalytic cysteine residue that confers antibiotic tolerance to these bacteria. Thus, the chemical tools and biological targets that we describe here prospect new therapeutic paradigms in combatting S. aureus infections.
Assuntos
Benzoquinonas/farmacologia , Compostos de Epóxi/farmacologia , Indóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Resistência a Vancomicina/efeitos dos fármacos , Antibacterianos/farmacologia , Benzoquinonas/química , Descoberta de Drogas , Compostos de Epóxi/química , Humanos , Indóis/química , Modelos Moleculares , Proteômica , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacologiaRESUMO
A thiol-selective 2-methyl-3-phenacrylate scaffold with spatiotemporal control over delivery of a cargo is reported. The half-lives of decomposition could be tuned from 30 min to 1 day and the scaffold's utility in thiol-inducible fluorophore release in cell-free as well as within cells is demonstrated.
