The Dynamic Influence of Olorofim (F901318) on the Cell Morphology and Organization of Living Cells of Aspergillus fumigatus
| Autor: | Nicola Beckmann, Jason David Oliver, Derek Law, Saskia du Pré, Graham Edward Morris Sibley, Mike Birch, Nick D. Read, Michael Bromley |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
pyrimidines Plant Science Vacuole Cell morphology Article Aspergillus fumigatus 03 medical and health sciences chemistry.chemical_compound fungal cell morphogenesis Olorofim Protein biosynthesis antifungal drugs olorofim lcsh:QH301-705.5 Mitosis Ecology Evolution Behavior and Systematics 030304 developmental biology Fungal cell morphogenesis 0303 health sciences biology 030306 microbiology DHODH biology.organism_classification Cell biology Thymine Pyrimidines lcsh:Biology (General) chemistry Dihydroorotate dehydrogenase Antifungal drugs Cytosine |
| Zdroj: | Journal of Fungi Volume 6 Issue 2 Journal of Fungi, Vol 6, Iss 47, p 47 (2020) du Pré, S, Birch, M, Law, D, Beckmann, N, Sibley, G E M, Bromley, M J, Read, N D & Oliver, J D 2020, ' The Dynamic Influence of Olorofim (F901318) on the Cell Morphology and Organization of Living Cells of Aspergillus fumigatus ', Journal of Fungi, vol. 6, no. 2, 47 . https://doi.org/10.3390/jof6020047 |
| ISSN: | 2309-608X |
| DOI: | 10.3390/jof6020047 |
| Popis: | The first characterized antifungal in the orotomide class is olorofim. It targets the de novo pyrimidine biosynthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH). The pyrimidines uracil, thymine and cytosine are the building blocks of DNA and RNA thus, inhibition of their synthesis is likely to have multiple effects, including affecting cell cycle regulation and protein synthesis. Additionally, uridine-5&prime triphosphate (UTP) is required for the formation of uridine-diphosphate glucose (UDP-glucose), which is an important precursor for several cell wall components. In this study, the dynamic effects of olorofim treatment on the morphology and organization of Aspergillus fumigatus hyphae were analyzed microscopically using confocal live-cell imaging. Treatment with olorofim led to increased chitin content in the cell wall, increased septation, enlargement of vacuoles and inhibition of mitosis. Furthermore, vesicle-like structures, which could not be stained or visualized with a range of membrane- or vacuole-selective dyes, were found in treated hyphae. A colocalization study of DHODH and MitoTracker Red FM confirmed for the first time that A. fumigatus DHODH is localized in the mitochondria. Overall, olorofim treatment was found to significantly influence the dynamic structure and organization of A. fumigatus hyphae. |
| Databáze: | OpenAIRE |
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