What question did this study set out to answer?

This research aims to evaluate the effectiveness of fluorene-based molecules as inhibitors of MRSA growth and to understand their mechanisms of action.

May 11, 2026Journal of Biological Chemistry0 citationsOpen Access

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

AGAvery GaudreauWestern University MBMatthew BecknerWestern University CSChenfangfei ShenWestern University

Key Points

This research aims to evaluate the effectiveness of fluorene-based molecules as inhibitors of MRSA growth and to understand their mechanisms of action.
High-throughput screening identified DB10 as a MRSA growth inhibitor.
Photochemical modification of DB10 and its analog DB33 was assessed for antimicrobial activity.
The compounds' effects on bacterial burden were tested in a murine skin infection model.
DB10-Y showed improved minimum inhibitory concentrations against Gram-positive bacteria.
DB33-Y reduced bacterial burden and lesion size in murine models.
Both compounds suppressed expression of -hemolysin at sub-MIC concentrations.

Abstract

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-coloured form (DB10-R) to a yellow-coloured form (DB10-Y).In comparison with DB10-R, DB10-Y exhibits reduced hydrophobicity, lower cytotoxicity, and modestly improved minimum inhibitory concentrations (MICs) towards several Gram-positive bacteria.DB10-Y intercalates into DNA and induces double-stranded 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 non-toxic 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 -hemolysin at sub-MIC concentrations, indicating an additional anti-virulence effect.Together, these findings highlight the therapeutic potential of fluorene-based DNA intercalators as a new class of antimicrobial and anti-virulence agents against MRSA.

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