In 2007, the Kock group published the Aspirin Antifungal Hypothesis showing a
clear link between oxylipin production, mitochondrial activity and acetylsalicylic
acid (ASA, aspirin) sensitivity in respiring as well as non-respiring yeasts. This
hypothesis suggests that mitochondrial inhibitors such as ASA selectively inhibits
parts of yeast life cycles, especially the sexual stage. According to the
hypothesis, mitochondrial β-oxidation products such as 3-OH oxylipins are
present in elevated amounts in yeast sexual structures (asci) and lesser amounts
in vegetative asexual structures (hyphae and single cells). This suggests
increased mitochondrial activity in asci. Consequently, ascomycetous yeast
sexual structures should be more sensitive to mitochondrial inhibitors compared
to vegetative asexual structures. The purpose of the study became to assess if
the Aspirin Antifungal Hypothesis could be expanded to also include other
mitochondrial inhibiting drugs as well as other structures present in fungal life
cycles where increased mitochondrial activities are expected. In this study, the
anti-inflammatory drugs ASA, ibuprofen, indomethacin, salicylic acid and benzoic
acid as well as anticancer drugs such as Lonidamine, also known for inhibiting
mitochondrial activity in mammalian cells, were found to be antifungal and
specifically target the sexual stage of yeast. This is shown by a unique yeast bioassay,
with the mitochondrion-dependent sexual dispersal structure producing
many ascospores, riboflavin production, and hyphal morphology of the notorious
yeast plant pathogen Eremothecium ashbyi serving as indicators. These drugs
affect this yeast in a similar way as found under oxygen limitation conditions by
inhibiting sexual structure development (most sensitive), riboflavin production,
and yielding characteristically wrinkled and granular hyphae, presenting a unique
âanoxicâ morphological pattern. Only drugs associated with mitochondrial inhibiting activity presented such a pattern. This bio-assay may find application in
the preliminary screening for novel drugs from various sources with possible
mitochondrial inhibiting actions. In another part of the study, the effects of antimitochondrial
compounds on asexual fungal spore dispersal structures in the
pathogens Aspergillus fumigatus and Rhizopus oryzae were investigated. When
anti-mitochondrial ASA and other anti-mitochondrial non-steroidal antiinflammatory
drugs (NSAIDs) were added to A. fumigatus and R. oryzae, asexual
fungal spore-releasing structures were targeted first at lower concentrations.
Similar results were obtained when oxygen was limited. These asexual fungal
spore-releasing structures contained increased levels of mitochondrial activity
compared to hyphae. Increased mitochondrial activity may be necessary for the
formation of asexual fungal spore dispersal structures of these fungi.
Consequently, mitochondrial inhibitors may serve as effective antifungals to
combat asexual fungal spore dispersal of these pathogenic fungi. In this study,
the Aspirin Antifungal Hypothesis is expanded to also include various antiinflammatory
compounds, anticancer drugs, plant extracts, traditional medicines
and others â many showing anti-mitochondrial activity. These compounds should
be further investigated to determine their minimum inhibitory concentrations
(MICs) and application to combat plant and human fungal pathogens. In this
study, the hypothesis is also expanded to include asexual fungal dispersal
structures with increased mitochondrial activity.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-10172011-125203 |
| Date | 17 October 2011 |
| Creators | Mbulelo, Ncango Desmond |
| Contributors | Dr CH Pohl, Prof PWJ van Wyk, Prof JLF Kock |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-10172011-125203/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0023 seconds