Laccase Regulators in Anti-fungal Drug Discovery: Dark Lessons from the AIDS-related Pathogen, Cryptococcus

Fungal infections afflict an increasing number of patients due to increases in susceptible immunosuppressed populations such as those receiving chemotherapy, transplant conditioning or infections such as HIV. Poor responses to available therapy have prompted searches for novel drug targets, but screens can be difficult as expression of these targets often relies on specific inducing conditions present within the mammalian host. Cryptococcus is a yeast-like basidiomycete fungus capable of causing fatal cryptococcocis in both immunocompetent and immunocompromised individuals, and is currently the fourth cause of infectious death in regions of Sub-Sahara Africa, excluding HIV. A key virulence factor of Cryptococcus is a cell-wall laccase, which produces melanin in the presence of exogenous catecholamines. Screening melanin-deficient strains of the fungus is facile and has identified cellular processes critical for virulence including copper homeostasis and autophagy. As demonstrated here through the analysis of laccase regulatory networks of Cryptococcus, genetic analysis targeting virulence-associated regulatory pathways can lead to the discovery of promising novel drug candidates against fungal species.