Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach

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, fungalspecific, 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.

The antifungal pipeline: a reality check

“…The calcineurin pathway is important in eukaryotes and is potentially a target of selective inhibitors that could become antifungal drugs 35,36 . The serine/threonine phosphatase calcineurin (also known as protein phosphatase 3; a hetero dimer that is composed of the subunits calcineurin A and calcineurin B) is the target for the most commonly used transplant anti-rejection drugs: tacrolimus and cyclosporine.…”

“…In this respect, the inhibitors must be fungicidal with minimal or no immunosuppressive activity. It has been helpful that the fungal and human homologues of calcineurin are well understood from a structural perspective 36 . It is with this knowledge and a concerted chemistry effort that progress is being made in discovering potent antifungal, anti-calcineurin molecules with reduced immuno suppressive activity; these are currently being tested in animal models 40 .…”

The putative flavin carrier family FlcA-C is important forAspergillus fumigatusvirulence

“…[1][2][3][4][5] The calcineurin phosphatase and the transcription factor Crz1p1/CrzA are essential for fungal calcium signaling. 1,2 In Saccharomyces cerevisiae, several environmental stresses, for instance osmotic, extreme pH, high temperature, ER stress and prolonged incubation with mating pheromone a-factor, are regulated by calcineurin. 5,6 Calcineurin also connects many stress response signaling pathways.…”

“…15 The signaling by calcium is very important for fungal virulence and drug resistance. 1,2 Calcineurin has been demonstrated to be required for virulence in human fungal pathogens, such as Cryptococcus spp, Candida spp, Paracoccidioides brasiliensis, and Aspergillus fumigatus; [16][17][18][19][20][21][22][23] and fungal plant pathogens, such as Sclerotinia scleotiorum, Botrytis cinerea, Magnaporthe oryza, and Ustilago spp. [24][25][26][27][28] In all these fungal pathogens, calcineurin is important for growth, morphology, state transitions, cation homeostasis, stress responses, and cell membrane and cell wall integrity pathways.…”

“…[24][25][26][27][28] In all these fungal pathogens, calcineurin is important for growth, morphology, state transitions, cation homeostasis, stress responses, and cell membrane and cell wall integrity pathways. 1,2,[29][30][31][32][33] Aspergillus fumigatus is an opportunistic fungal pathogen and the most important species causing pulmonary fungal infections. 15,[34][35][36][37][38] Although A. fumigatus is able to cause many clinical forms, the most important is the invasive pulmonary aspergillosis (IPA), that has mortality rates as high as 80% in immunosuppressed patients.…”