Evolution of 8-esterified cycloberberines as a novel class of antibacterial agents against MDR gram-positive strains by targeting DNA polymerase IIIC.

The constant evolution of Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) constitutes a major threat to human health with limited treatment options. In our previous studies, we invented an innovative cycloberberine (CBBR) scaffold to battle MRSA and other Gram-positive strains. Herein, we report the synthesis and biological evaluations of forty-four CBBR esters derivatives, of which forty-two were new, against Gram-positive pathogens. Compound 5a demonstrated superior in vitro potency against MRSA and VISA strains, with MIC values of 0.06-0.125 μg/mL, outperforming the reference drug levofloxacin (MIC range: 0.125-32 μg/mL). Meanwhile, it reduced the MRSA burden in murine skin infection model and decreased pro-inflammatory cytokine levels, exemplified as interleukin (IL)-1β and IL-6, in MRSA-infected wounds. Further mechanism study revealed its unique ability to inhibit bacterial genomic DNA replication by targeting DNA polymerase IIIC, distinct from the clinical antibiotics. Therefore, we consider CBBR ester derivatives to be a promising class of anti-MRSA agents worthy of further investigation.