Calcium signaling pathway is involved in non-CYP51 azole resistance in <i>Aspergillus fumigatus</i>

Li, Yeqi; Zhang, Yuanwei; Lü, Ling

doi:10.1093/mmy/myy075

Cited by 24 publications

(16 citation statements)

References 63 publications

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“…Although this molecular mechanism has been well characterized, little is known about other molecular mechanisms underlying resistance to azoles arising from mitochondrial dysfunction. It has been reported that calcium signaling is involved in azole resistance in various fungi [ 27 , 28 , 29 , 30 ]. Defects in calcium homeostasis would lead to the retention of cytoplasmic calcium, which in turn activates calcineurin phosphatase activity [ 27 ].…”

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

“…It has been reported that calcium signaling is involved in azole resistance in various fungi [ 27 , 28 , 29 , 30 ]. Defects in calcium homeostasis would lead to the retention of cytoplasmic calcium, which in turn activates calcineurin phosphatase activity [ 27 ]. The activated calcineurin will dephosphorylate zinc finger transcription factor Crz1, promoting nuclear translocation and induction of genes involved in azole resistance in Candida albicans [ 31 ].…”

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

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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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Section: Role Of Fungal Mitochondria In Azole Resistancementioning

confidence: 99%

Section: Role Of Fungal Mitochondria In Azole Resistancementioning

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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“…It was hypothesized that the fungistatic activity of azoles against A. fumigatus (rather than fungicidal) could promote the selection of resistant strains (20,21). Therefore, cotargeting the drug targets with fungal stress response regulators could be a promising strategy to enhance the efficacy of established antifungals and improve clinical outcomes (22). Moreover, nonantifungal compounds, such as the immunosuppressive drugs cyclosporine A (CsA), tacrolimus (FK506), and the heart-antiarrhythmic agent amiodarone with calcium channel blocker-like actions exhibit antifungal activity alone or in combination with antifungal drugs (23,24).…”

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confidence: 99%

Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Drug resistance in fungal pathogens has risen steadily over the past decades due to long-term azole therapy or triazole usage in agriculture. Modification of the drug target protein to prevent drug binding is a major recognized route to induce drug resistance. However, mechanisms for nondrug target-induced resistance remain only loosely defined. Here, we explore the molecular mechanisms of multidrug resistance resulted from an efficient adaptation strategy for survival in drug environments in the human pathogen Aspergillus fumigatus. We show that mutants conferring multidrug resistance are linked with mitochondrial dysfunction induced by defects in heme A biosynthesis. Comparison of the gene expression profiles between the drug-resistant mutants and the parental wild-type strain shows that multidrug-resistant transporters, chitin synthases, and calcium-signaling-related genes are significantly up-regulated, while scavenging mitochondrial reactive oxygen species (ROS)-related genes are significantly down-regulated. The up-regulated-expression genes share consensus calcium-dependent serine threonine phosphatase-dependent response elements (the binding sites of calcium-signaling transcription factor CrzA). Accordingly, drug-resistant mutants show enhanced cytosolic Ca2+ transients and persistent nuclear localization of CrzA. In comparison, calcium chelators significantly restore drug susceptibility and increase azole efficacy either in laboratory-derived or in clinic-isolated A. fumigatus strains. Thus, the mitochondrial dysfunction as a fitness cost can trigger calcium signaling and, therefore, globally up-regulate a series of embedding calcineurin-dependent–response-element genes, leading to antifungal resistance. These findings illuminate how fitness cost affects drug resistance and suggest that disruption of calcium signaling might be a promising therapeutic strategy to fight against nondrug target-induced drug resistance.

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“…Sphingolipid biosynthesis contributes to unfolded protein response (UPR) pathway‐mediated azole resistance . When fungal cells encounter azole drugs, they likely activate stress‐response pathways to protect the cells from damage (Kim et al ., 2019; Li et al ., 2019). To cope with azole stress, fungal cells activate the UPR signaling pathway, which is responsible for response to ER stress induced by azoles (Richie et al ., 2009; Cheon et al ., 2014; Krishnan and Askew, 2014; Miyazaki and Kohno, 2014).…”

Section: Role Of Fungal Sphingolipid Synthesis In Azole Resistancementioning

confidence: 99%

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

Song

Xiao

2020

Molecular Microbiology

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In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH-responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole-induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.

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Calcium signaling pathway is involved in non-CYP51 azole resistance in Aspergillus fumigatus

Cited by 24 publications

References 63 publications

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

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

Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

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