Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload
Abstract Invasive fungal infections are a growing public health threat. As fungi become increasingly resistant to existing drugs, new antifungals are urgently needed. Here, it is reported that 405‐nm‐visible‐light‐activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal p...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202205781 |
| _version_ | 1827972746372448256 |
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| author | Ana L. Santos Jacob L. Beckham Dongdong Liu Gang Li Alexis vanVenrooy Antonio Oliver George P. Tegos James M. Tour |
| author_facet | Ana L. Santos Jacob L. Beckham Dongdong Liu Gang Li Alexis vanVenrooy Antonio Oliver George P. Tegos James M. Tour |
| author_sort | Ana L. Santos |
| collection | DOAJ |
| description | Abstract Invasive fungal infections are a growing public health threat. As fungi become increasingly resistant to existing drugs, new antifungals are urgently needed. Here, it is reported that 405‐nm‐visible‐light‐activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal populations more effectively than conventional antifungals without resistance development. Mechanism‐of‐action studies show that MMs bind to fungal mitochondrial phospholipids. Upon visible light activation, rapid unidirectional drilling of MMs at ≈3 million cycles per second (MHz) results in mitochondrial dysfunction, calcium overload, and ultimately necrosis. Besides their direct antifungal effect, MMs synergize with conventional antifungals by impairing the activity of energy‐dependent efflux pumps. Finally, MMs potentiate standard antifungals both in vivo and in an ex vivo porcine model of onychomycosis, reducing the fungal burden associated with infection. |
| first_indexed | 2024-04-09T19:26:16Z |
| format | Article |
| id | doaj.art-1780bd3f43414cad8ce153aaed5e4040 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-09T19:26:16Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1780bd3f43414cad8ce153aaed5e40402023-04-05T08:09:48ZengWileyAdvanced Science2198-38442023-04-011010n/an/a10.1002/advs.202205781Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium OverloadAna L. Santos0Jacob L. Beckham1Dongdong Liu2Gang Li3Alexis vanVenrooy4Antonio Oliver5George P. Tegos6James M. Tour7Department of Chemistry Rice University Houston TX 77005 USADepartment of Chemistry Rice University Houston TX 77005 USADepartment of Chemistry Rice University Houston TX 77005 USADepartment of Chemistry Rice University Houston TX 77005 USADepartment of Chemistry Rice University Houston TX 77005 USAIdISBA – Fundación de Investigación Sanitaria de las Islas Baleares Palma 07120 SpainOffice of Research Reading Hospital Tower Health, 420 S. Fifth Avenue West Reading PA 19611 USADepartment of Chemistry Rice University Houston TX 77005 USAAbstract Invasive fungal infections are a growing public health threat. As fungi become increasingly resistant to existing drugs, new antifungals are urgently needed. Here, it is reported that 405‐nm‐visible‐light‐activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal populations more effectively than conventional antifungals without resistance development. Mechanism‐of‐action studies show that MMs bind to fungal mitochondrial phospholipids. Upon visible light activation, rapid unidirectional drilling of MMs at ≈3 million cycles per second (MHz) results in mitochondrial dysfunction, calcium overload, and ultimately necrosis. Besides their direct antifungal effect, MMs synergize with conventional antifungals by impairing the activity of energy‐dependent efflux pumps. Finally, MMs potentiate standard antifungals both in vivo and in an ex vivo porcine model of onychomycosis, reducing the fungal burden associated with infection.https://doi.org/10.1002/advs.202205781antifungalfungal mitochondrial phospholipidsmolecular machinesreduction of infection‐associated mortality and fungal burdenvisible light activation |
| spellingShingle | Ana L. Santos Jacob L. Beckham Dongdong Liu Gang Li Alexis vanVenrooy Antonio Oliver George P. Tegos James M. Tour Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload Advanced Science antifungal fungal mitochondrial phospholipids molecular machines reduction of infection‐associated mortality and fungal burden visible light activation |
| title | Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload |
| title_full | Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload |
| title_fullStr | Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload |
| title_full_unstemmed | Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload |
| title_short | Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload |
| title_sort | visible light activated molecular machines kill fungi by necrosis following mitochondrial dysfunction and calcium overload |
| topic | antifungal fungal mitochondrial phospholipids molecular machines reduction of infection‐associated mortality and fungal burden visible light activation |
| url | https://doi.org/10.1002/advs.202205781 |
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