Synthesis and antibacterial evaluation of trisindolines against methicillin-resistant Staphylococcus aureus targeting cell membrane

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global health threat that requires novel antimicrobials to combat this WHO-designated priority pathogen. In this study, we designed, synthesized and evaluated a series of unexplored trisindoline derivatives against MRSA, including multidrug-resistant (MDR) clinical isolates. The Structure Activity Relationship (SAR) analysis of the trisindolines indicated the importance of strategic substitutions in the trisindoline core for their anti-staphylococcal efficacy. Biocompatibility studies revealed a high safety profile for the active compounds across various mammalian cell lines. Furthermore, the derivatives displayed rapid bactericidal action, anti-biofilm efficacy, intracellular MRSA killing and combinatorial effect with vancomycin. Mechanistic studies revealed that these compounds disrupt MRSA cell integrity by influencing several membrane-related pathways. Finally, in vivo assessments of a lead trisindoline in an MRSA-induced systemic infection model demonstrated a significant reduction of bacterial load. Therefore, these trisindoline molecules may offer a promising therapeutic model for combating MRSA infections.