Indolocarbazoles as host-directed therapeutics against intracellular infections by methicillin-resistant...

Methicillin-resistant Staphylococcus aureus (MRSA) is a principal contributor to mortality and morbidity attributable to antimicrobial resistance. Many MRSA strains are able to invade host cells, thereby further evading antibiotic treatment. Previously, indolocarbazole GW296115X was identified as a hit compound with host-directed activity against intracellular MRSA. This study evaluates the efficacy and selectivity of indolocarbazoles as potential host-directed therapy against intracellular MRSA. Furthermore, we assessed the interaction between indolocarbazoles and standard-of-care antibiotics.

Bioluminescent luxBADCE-expressing MRSA was used to evaluate antimicrobial activity in planktonic cultures and HeLa cell intracellular infection models. Drug safety was assessed through lactate dehydrogenase (LDH) release and WST-1 cytotoxicity assays. The interaction between selected indolocarbazoles in combination with vancomycin or daptomycin was determined based on the Bliss independence model.

Indolocarbazoles GW296115X, staurosporine aglycone, CDK4 inhibitor and SB-218078 showed activity against intracellular MRSA with SB-218078 demonstrating the best potency. None of the effective compounds impaired host cell viability, although host cell metabolic activity was affected to various extents. Combining SB-218078 or GW296115X with vancomycin or daptomycin synergistically eradicated both intracellular and extracellular MRSA.

Indolocarbazoles, particularly GW296115X and SB-218078, enhance standard antibiotic efficacy against invasive MRSA and offer potential for host-directed therapy.