Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study
The opportunistic yeast Candida albicans is the most common cause of candidiasis. With only four classes of antifungal drugs on the market, resistance is becoming a problem in the treatment of fungal infections, especially in immunocompromised patients. The development of novel antifungal drugs with...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1141785/full |
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| author | Kai Hilpert Christoph Rumancev Jurnorain Gani Dominic W. P. Collis Paula Matilde Lopez-Perez Vasil M. Garamus Ralf Mikut Axel Rosenhahn |
| author_facet | Kai Hilpert Christoph Rumancev Jurnorain Gani Dominic W. P. Collis Paula Matilde Lopez-Perez Vasil M. Garamus Ralf Mikut Axel Rosenhahn |
| author_sort | Kai Hilpert |
| collection | DOAJ |
| description | The opportunistic yeast Candida albicans is the most common cause of candidiasis. With only four classes of antifungal drugs on the market, resistance is becoming a problem in the treatment of fungal infections, especially in immunocompromised patients. The development of novel antifungal drugs with different modes of action is urgent. In 2016, we developed a groundbreaking new medium-throughput method to distinguish the effects of antibacterial agents. Using small-angle X-ray scattering for biological samples (BioSAXS), it is now possible to screen hundreds of new antibacterial compounds and select those with the highest probability for a novel mode of action. However, yeast (eukaryotic) cells are highly structured compared to bacteria. The fundamental question to answer was if the ultrastructural changes induced by the action of an antifungal drug can be detected even when most structures in the cell stay unchanged. In this exploratory work, BioSAXS was used to measure the ultrastructural changes of C. albicans that were directly or indirectly induced by antifungal compounds. For this, the well-characterized antifungal drug Flucytosine was used. BioSAXS measurements were performed on the synchrotron P12 BioSAXS beamline, EMBL (DESY, Hamburg) on treated and untreated yeast C. albicans. BioSAXS curves were analysed using principal component analysis (PCA). The PCA showed that Flucytosine-treated and untreated yeast were separated. Based on that success further measurements were performed on five antifungal peptides {1. Cecropin A-melittin hybrid [CA (1–7) M (2–9)], KWKLFKKIGAVLKVL; 2. Lasioglossin LL-III, VNWKKILGKIIKVVK; 3. Mastoparan M, INLKAIAALAKKLL; 4. Bmkn2, FIGAIARLLSKIFGKR; and 5. optP7, KRRVRWIIW}. The ultrastructural changes of C. albicans indicate that the peptides may have different modes of action compared to Flucytosine as well as to each other, except for the Cecropin A-melittin hybrid [CA (1–7) M (2–9)] and optP7, showing very similar effects on C. albicans. This very first study demonstrates that BioSAXS shows promise to be used for antifungal drug development. However, this first study has limitations and further experiments are necessary to establish this application. |
| first_indexed | 2024-03-12T23:09:22Z |
| format | Article |
| id | doaj.art-28cfbb9bce624ba28163d372edca6fb1 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T23:09:22Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-28cfbb9bce624ba28163d372edca6fb12023-07-18T08:22:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-07-011410.3389/fphar.2023.11417851141785Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory studyKai Hilpert0Christoph Rumancev1Jurnorain Gani2Dominic W. P. Collis3Paula Matilde Lopez-Perez4Vasil M. Garamus5Ralf Mikut6Axel Rosenhahn7Institute of Infection and Immunology, St. George’s, University of London (SGUL), London, United KingdomLaboratory Analytical Chemistry—Biointerfaces, Ruhr-University Bochum, Bochum, GermanyInstitute of Infection and Immunology, St. George’s, University of London (SGUL), London, United KingdomTiKa Diagnostics Ltd., London, United KingdomTiKa Diagnostics Ltd., London, United KingdomHelmholtz-Zentrum Hereon, Geesthacht, GermanyInstitute for Automation and Applied Informatics (IAI), Karlsruhe Institute of Technology (KIT), Karlsruhe, GermanyLaboratory Analytical Chemistry—Biointerfaces, Ruhr-University Bochum, Bochum, GermanyThe opportunistic yeast Candida albicans is the most common cause of candidiasis. With only four classes of antifungal drugs on the market, resistance is becoming a problem in the treatment of fungal infections, especially in immunocompromised patients. The development of novel antifungal drugs with different modes of action is urgent. In 2016, we developed a groundbreaking new medium-throughput method to distinguish the effects of antibacterial agents. Using small-angle X-ray scattering for biological samples (BioSAXS), it is now possible to screen hundreds of new antibacterial compounds and select those with the highest probability for a novel mode of action. However, yeast (eukaryotic) cells are highly structured compared to bacteria. The fundamental question to answer was if the ultrastructural changes induced by the action of an antifungal drug can be detected even when most structures in the cell stay unchanged. In this exploratory work, BioSAXS was used to measure the ultrastructural changes of C. albicans that were directly or indirectly induced by antifungal compounds. For this, the well-characterized antifungal drug Flucytosine was used. BioSAXS measurements were performed on the synchrotron P12 BioSAXS beamline, EMBL (DESY, Hamburg) on treated and untreated yeast C. albicans. BioSAXS curves were analysed using principal component analysis (PCA). The PCA showed that Flucytosine-treated and untreated yeast were separated. Based on that success further measurements were performed on five antifungal peptides {1. Cecropin A-melittin hybrid [CA (1–7) M (2–9)], KWKLFKKIGAVLKVL; 2. Lasioglossin LL-III, VNWKKILGKIIKVVK; 3. Mastoparan M, INLKAIAALAKKLL; 4. Bmkn2, FIGAIARLLSKIFGKR; and 5. optP7, KRRVRWIIW}. The ultrastructural changes of C. albicans indicate that the peptides may have different modes of action compared to Flucytosine as well as to each other, except for the Cecropin A-melittin hybrid [CA (1–7) M (2–9)] and optP7, showing very similar effects on C. albicans. This very first study demonstrates that BioSAXS shows promise to be used for antifungal drug development. However, this first study has limitations and further experiments are necessary to establish this application.https://www.frontiersin.org/articles/10.3389/fphar.2023.1141785/fullCandida albicansantifungal peptidesantimicrobial peptidesBioSAXSSAXS (small-angle X-ray scattering)mode of action (MOA) |
| spellingShingle | Kai Hilpert Christoph Rumancev Jurnorain Gani Dominic W. P. Collis Paula Matilde Lopez-Perez Vasil M. Garamus Ralf Mikut Axel Rosenhahn Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study Frontiers in Pharmacology Candida albicans antifungal peptides antimicrobial peptides BioSAXS SAXS (small-angle X-ray scattering) mode of action (MOA) |
| title | Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study |
| title_full | Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study |
| title_fullStr | Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study |
| title_full_unstemmed | Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study |
| title_short | Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study |
| title_sort | can biosaxs detect ultrastructural changes of antifungal compounds in candida albicans an exploratory study |
| topic | Candida albicans antifungal peptides antimicrobial peptides BioSAXS SAXS (small-angle X-ray scattering) mode of action (MOA) |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1141785/full |
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