Murphy, Sarah;
(2020)
Investigating a novel antifungal drug that inhibits fatty acid desaturation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Invasive fungal infections represent a group of diseases that are of increasing worldwide concern. This group of diseases is associated with high mortality rates that can be attributed to widespread clinical drug resistance. Of significant concern, resistance has been recorded against every licenced clinical treatment. F900742 is a member of a novel and hopeful antifungal drug class that exerts activity through the inhibition of fatty acid desaturation. It is likely that F900742 directly targets the fatty acid desaturase 9 desaturase. F900742 demonstrated broad-spectrum antifungal activity in vitro and in vivo G. mellonella studies at low doses of drug. Ultrastructural analysis established that the inhibition of the OLE1 pathway induced the rapid formation of previously unidentified, lipid-dependent structures that are derived from the ER. It is predicted that these compartments are high in saturated acyl chain content. The sole 9 desaturase in the budding yeast Saccharomyces cerevisiae, Ole1p, relocalised to areas consistent with the aberrant structures. This investigation characterised a novel cellular response to acute inhibition of fatty acid desaturation through the formation of lipo-protective compartments that sequester toxic levels of saturated lipids. F900742 also induced mitochondrial fission and significant ROS production. Together this data suggested that the mechanism of action of F900742 is via lipid-dependent responses that quickly alters the lipidome in favour of saturated lipid content which induces ER and mitochondrial morphological phenotypes and subsequent activation of processes such as ROS production and the UPR.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating a novel antifungal drug that inhibits fatty acid desaturation |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10089214 |
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