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Review
, 8 (2), 186-197

Calcineurin in Fungal Virulence and Drug Resistance: Prospects for Harnessing Targeted Inhibition of Calcineurin for an Antifungal Therapeutic Approach

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Review

Calcineurin in Fungal Virulence and Drug Resistance: Prospects for Harnessing Targeted Inhibition of Calcineurin for an Antifungal Therapeutic Approach

Praveen R Juvvadi et al. Virulence.

Abstract

Increases in the incidence and mortality due to the major invasive fungal infections such as aspergillosis, candidiasis and cryptococcosis caused by the species of Aspergillus, Candida and Cryptococcus, are a growing threat to the immunosuppressed patient population. In addition to the limited armamentarium of the current classes of antifungal agents available (pyrimidine analogs, polyenes, azoles, and echinocandins), their toxicity, efficacy and the emergence of resistance are major bottlenecks limiting successful patient outcomes. Although these drugs target distinct fungal pathways, there is an urgent need to develop new antifungals that are more efficacious, fungal-specific, with reduced or no toxicity and simultaneously do not induce resistance. Here we review several lines of evidence which indicate that the calcineurin signaling pathway, a target of the immunosuppressive drugs FK506 and cyclosporine A, orchestrates growth, virulence and drug resistance in a variety of fungal pathogens and can be exploited for novel antifungal drug development.

Keywords: FK506; FKBP12; Hsp90; antifungals; azoles; calcineurin; cyclosporine A; drug resistance; echinocandins; virulence.

Figures

Figure 1.
Figure 1.
Schematic representation of the calcineurin signaling pathway. In response to external stimuli Ca2+ ions enter the cell through the high affinity calcium channels, Cch1 and Mid1. Upon binding to 4 Ca2+ ions the calcium-binding protein, calmodulin (CaM), undergoes a conformational change. Activated Ca2+-calmodulin complex binds to the calcineurin heterodimer (CnA and CnB) and enhances the calcineurin phosphatase activity. The activity of calcineurin is inhibited by the binding of the immunophilin-immunosuppresant complexes (FK506-FKBP12 and CsA-CypA). The activated calcineurin complex dephosphorylates the calcineurin-dependent transcription factor, Crz1, and enables its translocation into the nucleus. Crz1 activates the transcription of genes involved in the regulation of stress response, cell wall integrity, growth and drug resistance.

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