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Photochemical modification of two fluorene-based molecules with DNA intercalating and anti-methicillin resistant
Avery Gaudreau1, Matthew D Beckner1, Chenfangfei Shen2
1Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
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 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.
Insights
New fluorene-based compounds, DB10 and DB33, show promise as antimicrobials against methicillin-resistant Staphylococcus aureus (MRSA). These compounds target bacterial DNA and reduce virulence factors, offering a potential new strategy for combating drug-resistant infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Staphylococcus aureus, including methicillin-resistant strains (MRSA), poses a significant global health threat due to rising antibiotic resistance.
- Existing treatments are becoming less effective, necessitating the development of novel antimicrobials with unique mechanisms of action.
Purpose of the Study:
- To identify and characterize novel fluorene-based compounds with antimicrobial activity against MRSA.
- To investigate the mechanism of action and therapeutic potential of these compounds, including their anti-virulence effects.
Main Methods:
- High-throughput screening identified fluorene-based compound DB10 as an MRSA growth inhibitor.
- Photoconversion of DB10 to DB10-Y was studied, along with its properties and DNA intercalation.
- Fluorene analogs were screened, leading to the identification of DB33 and its active form DB33-Y.
- In vitro and in vivo efficacy of DB10-Y and DB33-Y were evaluated in cellular models and a murine skin infection model.
Main Results:
- DB10-Y, a photoconverted form of DB10, demonstrated antimicrobial activity, reduced cytotoxicity, and DNA intercalation.
- DB33-Y, an optimized analog, showed efficacy against intracellular MRSA and reduced bacterial burden in vivo.
- Both compounds exhibited anti-virulence effects by suppressing alpha-hemolysin expression at sub-inhibitory concentrations.
Conclusions:
- Fluorene-based DNA intercalators represent a promising new class of antimicrobial and anti-virulence agents.
- DB33-Y demonstrates significant potential for treating MRSA infections, including intracellular and skin infections.
- The dual action of DNA damage and virulence suppression offers a robust strategy against resistant bacteria.
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