2019
DOI: 10.1016/j.bcp.2019.01.012
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Targeting intrinsic cell death pathways to control fungal pathogens

Abstract: Fungal pathogens pose an increasing threat to public health. Limited clinical drug regimens and emerging drug-resistant isolates challenge infection control. The global burden of human fungal pathogens is estimated at 1 billion infections and 1.5 million deaths annually. In addition, plant fungal pathogens increasingly threaten global food resources. Novel strategies are needed to combat emerging fungal diseases and pan-resistant fungi. An untapped mechanistically novel approach is to pharmacologically activat… Show more

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Cited by 26 publications
(23 citation statements)
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References 165 publications
(207 reference statements)
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“…Thus, we conclude that C 18 -SMe 2 + affects complex I, and that the C 18 -alkyl chain is required for this unique activity. Increasing evidence suggests that fungi can undergo apoptotic cell death 17,18 , and mROS induces this pathway 38,42 . Thus, we tested for apoptosis in Z. tritici cells, treated with C 12 -G + , C 18 -NMe 3 + and C 18 -SMe 2 + .…”
Section: Resultsmentioning
confidence: 99%
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“…Thus, we conclude that C 18 -SMe 2 + affects complex I, and that the C 18 -alkyl chain is required for this unique activity. Increasing evidence suggests that fungi can undergo apoptotic cell death 17,18 , and mROS induces this pathway 38,42 . Thus, we tested for apoptosis in Z. tritici cells, treated with C 12 -G + , C 18 -NMe 3 + and C 18 -SMe 2 + .…”
Section: Resultsmentioning
confidence: 99%
“…Moreover, such chemistries must provide sustained control over the seasons, ideally having multi-site modes of action that cannot be easily overcome by the emergence of resistance 3 . Mitochondria are valuable targets for fungicide development, as these organelles provide cellular ATP, but also control lipid homeostasis and programmed fungal cell death 14,18 . In this study, we synthesized and investigated a group of MALCs, including variants with a dimethylsulfonium head group.…”
Section: Discussionmentioning
confidence: 99%
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“…In future work, investigations into the molecular mechanisms of rcd-1 -induced cell death are of major interest as the gene is active in a developmental stage (asexual spores) frequently associated with threats to human and plant health. Targeting of endogenous cell-death pathways in fungi could represent a viable strategy in the fight against various fungal pathogens; it was recently proposed that mice clear inhaled spores from their lungs by targeting fungal PCD (Shlezinger et al 2017; Kulkarni et al 2019). The identification of rcd-1 diversifies the inventory of allorecognition genes identified in fungi.…”
Section: Discussionmentioning
confidence: 99%
“…While PCD pathways are evolutionarily conserved throughout metazoa, fungi do not express homologous proteins implicated in these pathways. J. Marie Hardwick (The Johns Hopkins University School of Medicine, USA) discussed this divergence, noting that fungi contain their pro‐death proteins in vesicles, which are regulated by trafficking mechanisms . Hardwick's group is focused on studying the regulation of these ‘killer cargo’ vesicles and the signals which result in their fusion and the subsequent release of their contents.…”
Section: Pathways Off Broadwaymentioning
confidence: 99%