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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]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Photochemical modification of two fluorene-based molecules with DNA intercalating and anti-methicillin resistant Staphylococcus aureus activity.
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  Data: <searchLink fieldCode="AR" term="%22Gaudreau%2C+Avery%22">Gaudreau, Avery</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Beckner%2C+Matthew+D%2E%22">Beckner, Matthew D.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Shen%2C+Chenfangfei%22">Shen, Chenfangfei</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Du%2C+Vincent%22">Du, Vincent</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Flannagan%2C+Ronald+S%2E%22">Flannagan, Ronald S.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Balaji%2C+Varsha%22">Balaji, Varsha</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Papalambropoulos%2C+Evangelos%22">Papalambropoulos, Evangelos</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22El-Halfawy%2C+Omar+M%2E%22">El-Halfawy, Omar M.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Gillies%2C+Elizabeth+R%2E%22">Gillies, Elizabeth R.</searchLink><relatesTo>2,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Heinrichs%2C+David+E%2E%22">Heinrichs, David E.</searchLink><relatesTo>1</relatesTo><i> deh@uwo.ca</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Jun2026, Vol. 302 Issue 6, p1-20. 20p.
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  Data: <searchLink fieldCode="DE" term="%22Fluorene+compounds%22">Fluorene compounds</searchLink><br /><searchLink fieldCode="DE" term="%22Methicillin-resistant+staphylococcus+aureus%22">Methicillin-resistant staphylococcus aureus</searchLink><br /><searchLink fieldCode="DE" term="%22Photosensitization%22">Photosensitization</searchLink><br /><searchLink fieldCode="DE" term="%22Antibacterial+agents%22">Antibacterial agents</searchLink><br /><searchLink fieldCode="DE" term="%22Anti-infective+agents%22">Anti-infective agents</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-protein+interactions%22">DNA-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Skin+infections%22">Skin infections</searchLink>
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  Data: 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]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1016/j.jbc.2026.113133
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      – Code: eng
        Text: English
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        PageCount: 20
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    Subjects:
      – SubjectFull: Fluorene compounds
        Type: general
      – SubjectFull: Methicillin-resistant staphylococcus aureus
        Type: general
      – SubjectFull: Photosensitization
        Type: general
      – SubjectFull: Antibacterial agents
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      – SubjectFull: Anti-infective agents
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      – SubjectFull: DNA-protein interactions
        Type: general
      – SubjectFull: Skin infections
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      – TitleFull: Photochemical modification of two fluorene-based molecules with DNA intercalating and anti-methicillin resistant Staphylococcus aureus activity.
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              Text: Jun2026
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