The influence of mitochondrial inhibitors on fungal life cycles

[摘要] English: 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 'anoxic 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 �?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.

[发布机构] University of the Free State