eprintid: 10089214
rev_number: 45
eprint_status: archive
userid: 608
dir: disk0/10/08/92/14
datestamp: 2020-01-08 17:15:17
lastmod: 2021-02-01 07:10:36
status_changed: 2020-02-28 14:42:54
type: thesis
metadata_visibility: show
creators_name: Murphy, Sarah
title: Investigating a novel antifungal drug that inhibits fatty acid desaturation
ispublished: unpub
divisions: UCL
divisions: A01
divisions: B02
divisions: C07
note: © 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.
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.
date: 2020-01-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_open
thesis_award: Ph.D
language: eng
thesis_view: UCL_Thesis
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1738457
lyricists_name: Murphy, Sarah
lyricists_id: SMURP04
actors_name: Murphy, Sarah
actors_id: SMURP04
actors_role: owner
full_text_status: public
pages: 286
event_title: UCL
institution: UCL (University College London)
department: Institute of Ophthalmology
thesis_type: Doctoral
citation:        Murphy, Sarah;      (2020)    Investigating a novel antifungal drug that inhibits fatty acid desaturation.                   Doctoral thesis  (Ph.D), UCL (University College London).     Green open access   
 
document_url: https://discovery-pp.ucl.ac.uk/id/eprint/10089214/1/Murphy%2010089214%20PhD%20Thesis.%20Final.pdf