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

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Title: Photochemical modification of two fluorene-based molecules with DNA intercalating and anti-methicillin resistant Staphylococcus aureus activity.
Authors: Gaudreau, Avery1, Beckner, Matthew D.1, Shen, Chenfangfei2, Du, Vincent1, Flannagan, Ronald S.1, Balaji, Varsha1, Papalambropoulos, Evangelos1, El-Halfawy, Omar M.3, Gillies, Elizabeth R.2,4, Heinrichs, David E.1 deh@uwo.ca
Source: Journal of Biological Chemistry. Jun2026, Vol. 302 Issue 6, p1-20. 20p.
Subjects: Fluorene compounds, Methicillin-resistant staphylococcus aureus, Photosensitization, Antibacterial agents, Anti-infective agents, DNA-protein interactions, Skin infections
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-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 a-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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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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-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 a-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. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1016/j.jbc.2026.113133