Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach.
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.
a Department of Pediatrics , Division of Pediatric Infectious Diseases, Duke University School of Medicine , Durham , NC , USA.
Praveen R
PR
Juvvadi
b Department of Molecular Genetics & Microbiology , Duke University School of Medicine , Durham , NC , USA.
Soo Chan
SC
Lee
b Department of Molecular Genetics & Microbiology , Duke University School of Medicine , Durham , NC , USA.|c Department of Medicine , Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham , NC , USA.
Joseph
J
Heitman
a Department of Pediatrics , Division of Pediatric Infectious Diseases, Duke University School of Medicine , Durham , NC , USA.|b Department of Molecular Genetics & Microbiology , Duke University School of Medicine , Durham , NC , USA.
William J
WJ
Steinbach
D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D016572:Cyclosporine / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods*; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000627:therapeutic use; D005658:Fungi / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000627:therapeutic use; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D014774:Virulence
D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D054714:Echinocandins; D018841:HSP90 Heat-Shock Proteins; D016572:Cyclosporine; D019703:Calcineurin; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus
FK506; FKBP12; Hsp90; antifungals; azoles; calcineurin; cyclosporine A; drug resistance; echinocandins; virulence