Exploiting mitochondria as targets for the development of new antifungals

Li, Dongmei; Calderone, Richard

doi:10.1080/21505594.2016.1188235

Cited by 55 publications

(47 citation statements)

References 49 publications

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“…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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A lipophilic cation protects crops against fungal pathogens by multiple modes of action

et al. 2020

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The emerging resistance of crop pathogens to fungicides poses a challenge to food security and compels discovery of new antifungal compounds. Here, we show that mono-alkyl lipophilic cations (MALCs) inhibit oxidative phosphorylation by affecting NADH oxidation in the plant pathogens Zymoseptoria tritici, Ustilago maydis and Magnaporthe oryzae. One of these MALCs, consisting of a dimethylsulfonium moiety and a long alkyl chain (C18-SMe2+), also induces production of reactive oxygen species at the level of respiratory complex I, thus triggering fungal apoptosis. In addition, C18-SMe2+ activates innate plant defense. This multiple activity effectively protects cereals against Septoria tritici blotch and rice blast disease. C18-SMe2+ has low toxicity in Daphnia magna, and is not mutagenic or phytotoxic. Thus, MALCs hold potential as effective and non-toxic crop fungicides.

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Section: Discussionmentioning

confidence: 99%

“…Fungal mitochondria differ from their mammalian counterparts in composition and respiratory enzyme inventory [11][12][13] . This makes them an attractive target for fungicide development 14 ; indeed, two of the market leader singletarget site fungicides, the SDHIs and strobilurins, disrupt the fungal mitochondrial respiration chain 8 ( Supplementary Fig. 1a).…”

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confidence: 99%

A lipophilic cation protects crops against fungal pathogens by multiple modes of action

et al. 2020

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“…However, they prove to be a central hub for C. albicans physiology as their functionality affects not only the energy metabolism and central carbon metabolism but also the biosynthesis of constituents of the cell membrane and the cell wall and the susceptibility to drugs. Thus, inhibition of mitochondrial functions is nowadays discussed as a new target for antifungals (14,(24)(25)(26)(27). Previous studies were mainly focused on fungus-specific proteins, particularly those affecting the activity of complex I of the respiratory chain.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Respiration of Candida albicans by Small Molecules Increases Phagocytosis Efficacy by Macrophages

Cui

Hassan

et al. 2020

mSphere

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Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and structure of the fungal cell wall. Numerous studies had shown linkages between mitochondrial functionality, cell wall integrity and structure, and pathogenicity. Thus, we decided to inhibit single complexes of the respiratory chain of C. albicans and to analyze the resultant interaction with macrophages via their phagocytic activity. Remarkably, inhibition of the fungal bc1 complex by antimycin A increased phagocytosis, which correlated with an increased accessibility of β-glucans. To contribute to mechanistic insights, we performed metabolic studies, which highlighted significant changes in the abundance of constituents of the plasma membrane. Collectively, our results reinforce the strong linkage between fungal energy metabolism and other components of fungal physiology, which also determine the vulnerability to immune defense reactions. IMPORTANCE The yeast Candida albicans is one of the major fungal human pathogens, for which new therapeutic approaches are required. We aimed at enhancements of the phagocytosis efficacy of macrophages by targeting the cell wall structure of C. albicans, as the coverage of the β-glucan layer by mannans is one of the immune escape mechanisms of the fungus. We unambiguously show that inhibition of the fungal bc1 complex correlates with increased accessibilities of β-glucans and improved phagocytosis efficiency. Metabolic studies proved not only the known direct effects on reactive oxygen species (ROS) production and fermentative pathways but also the clear downregulation of the ergosterol pathway and upregulation of unsaturated fatty acids. The changed composition of the plasma membrane could also influence the interaction with the overlying cell wall. Thus, our work highlights the far-reaching relevance of energy metabolism, indirectly also for host-pathogen interactions, without affecting viability.

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“…While deep investigations are required to validate that Mge1 and/or the mitochondrial protein import complex as a target of HSA, previous elegant investigations in C. albicans have shown that many fungal mitochondrial proteins are therapeutic targets for antifungal development 61 . Furthermore, Mge1 has been recently shown to be a key regulator of azole susceptibility 62 which make the fungal mitochondria as an attractive organelle target to develop anti-virulence, anti-growth and anti-resistance molecules to manage fungal infection.…”

Section: Discussionmentioning

confidence: 99%

A phenotypic small-molecule screen identifies halogenated salicylanilides as inhibitors of fungal morphogenesis, biofilm formation and host cell invasion

García

Burgain

Chaillot

et al. 2018

Preprint

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A poorly exploited paradigm in the antimicrobial therapy field is to target virulence traits for drug development. In contrast to target-focused approaches, antivirulence phenotypic screens enable identification of bioactive molecules that induce a desirable biological readout without making a priori assumption about the cellular target. Here, we screened a chemical library of 678 small molecules against the invasive hyphal growth of the human opportunistic yeast Candida albicans. We found that a halogenated salicylanilide (N1-(3,5-dichlorophenyl)-5-chloro-2-hydroxybenzamide) and one of its analog, Niclosamide, an FDA-approved anthelmintic in humans, exhibited both antifilamentation and antibiofilm activities against C. albicans and the multi-resistant yeast C. auris. The antivirulence activity of halogenated salicylanilides were also expanded to C. albicans resistant strains with different resistance mechanisms. We also found that Niclosamide protected the intestinal epithelial cells against invasion by C. albicans. Transcriptional profiling of C. albicans challenged with Niclosamide exhibited a signature that is characteristic of the mitochondria-to-nucleus retrograde response. Our chemogenomic analysis showed that halogenated salicylanilides compromise the potential-dependant mitochondrial protein translocon machinery. Given the fact that the safety of Niclosamide is well established in humans, this molecule could represent the first clinically approved antivirulence agent against a pathogenic fungus.

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Exploiting mitochondria as targets for the development of new antifungals

Cited by 55 publications

References 49 publications

A lipophilic cation protects crops against fungal pathogens by multiple modes of action

A lipophilic cation protects crops against fungal pathogens by multiple modes of action

Inhibition of Respiration of Candida albicans by Small Molecules Increases Phagocytosis Efficacy by Macrophages

A phenotypic small-molecule screen identifies halogenated salicylanilides as inhibitors of fungal morphogenesis, biofilm formation and host cell invasion

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