Photochemical modification of two fluorene-based molecules with DNA intercalating and anti-methicillin resistant Staphylococcus aureus activity

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Staphylococcus aureus is a leading cause of skin and soft tissue infections, endocarditis, and bloodstream infections worldwide. The emergence of methicillin-resistant S. aureus (MRSA) and growing resistance to last-resort antibiotics like vancomycin have created an urgent need for new antimicrobials with distinct mechanisms of action. In this study, we characterize DB10, a planar, fluorene-based compound identified in a high-throughput screen for MRSA growth inhibitors. Upon UVA exposure, DB10 undergoes photoconversion from a red-colored form (DB10-R) to a yellow-colored form (DB10-Y). In comparison with DB10-R, DB10-Y exhibits reduced hydrophobicity, lower cytotoxicity, and modestly improved minimum inhibitory concentrations toward several Gram-positive bacteria. DB10-Y intercalates into DNA and induces double-strand breaks within bacterial cells, and resistance emerged only at low levels after prolonged serial passaging. To optimize this scaffold, we screened a panel of fluorene analogs and identified the photoconverting analog DB33, which in its yellow form (DB33-Y) is nontoxic and retained DNA intercalating activity. DB33-Y was effective against intracellular S. aureus in macrophages and endothelial cells and significantly reduced bacterial burden and lesion size in a murine skin infection model. DB10-Y and DB33-Y both also suppressed expression of α-hemolysin at sub-minimum inhibitory concentrations, indicating an additional antivirulence effect. Together, these findings highlight the therapeutic potential of fluorene-based DNA intercalators as a new class of antimicrobial and antivirulence agents against MRSA.

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