The potential of respiration inhibition as a new approach to combat human fungal pathogens

Duvenage, Lucian; Munro, Carol A.; Gourlay, Campbell W.

doi:10.1007/s00294-019-01001-w

Cited by 36 publications

(35 citation statements)

References 55 publications

(60 reference statements)

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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%

“…However, the existing studies are focused on fungus-specific complexes of the respiratory chain, such as the alternative oxidases (10,14), or on the link to morphology (15), the major virulence factor of C. albicans. The role of components of the classical respiratory chain in the cell wall structure and, thus, in the interaction with host cells, is yet largely underexplored.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…The existence of an alternative respiratory pathway, alternative oxidase (AOX), present in some Candida species, especially C. albicans has been implicated in reduced susceptibility to azoles and resistance to oxidative stress [137,138]. Although the inhibition of this alternative respiratory pathway might seem an attractive strategy to combat Candida infections, some authors state that this inhibition may result in different outcomes in turns of other drug susceptibilities, in which the link between mitochondrial respiration and cell wall regulation may vary among species [139,140].…”

Section: Cell Plasticitymentioning

confidence: 99%

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

2020

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Candida albicans represents the most frequent isolated yeast from bloodstream infections. Despite the remarkable progress in diagnostic and therapeutic approaches, these infections continue to be a critical challenge in intensive care units worldwide. The economic cost of bloodstream fungal infections and its associated mortality, especially in debilitated patients, remains unacceptably high. Candida albicans is a highly adaptable microorganism, being able to develop resistance following prolonged exposure to antifungals. Formation of biofilms, which diminish the accessibility of the antifungal, selection of spontaneous mutations that increase expression or decreased susceptibility of the target, altered chromosome abnormalities, overexpression of multidrug efflux pumps and the ability to escape host immune defenses are some of the factors that can contribute to antifungal tolerance and resistance. The knowledge of the antifungal resistance mechanisms can allow the design of alternative therapeutically options in order to modulate or revert the resistance. We have focused this review on the main factors that are involved in antifungal resistance and tolerance in patients with C. albicans bloodstream infections.

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“…Mitochondria house and integrate multiple metabolic functions relating to lipids, iron metabolism, energy production, and cell wall biosynthesis [ 14 , 15 , 16 , 17 , 18 , 19 ], which are associated with fungal virulence and resistance to azoles. Mutations affecting mitochondrial functions including functioning of the electron transport chain (ETC), protein import, calcium homeostasis, mitochondrial genome maintenance, and mitochondrial transcription can result in avirulence and azole resistance or susceptibility [ 17 , 20 , 21 , 22 , 23 , 24 , 25 ]. The functions of mitochondria in these pathways are complex, and research findings open avenues for new, mitochondria-targeted therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

Song

Zhou

Zhang³

et al. 2020

Microorganisms

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In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.

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The potential of respiration inhibition as a new approach to combat human fungal pathogens

Cited by 36 publications

References 55 publications

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

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

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

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