Laccase Regulators in Anti-fungal Drug Discovery: Dark Lessons from the AIDS-related Pathogen, Cryptococcus
Jennifer Rabjohns and Peter R. Williamson
Affiliation: 9000 Rockville Pike, Building 10, Rm 11N234, MSC 1888, Bethesda, MD 20892. USA.
Keywords: AIDS, biological markers, clinical markers, Cryptococcus, drug design, laccase, regulation, review.
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.
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