Cryptococcus neoformans is pathogenic yeast that primarily causes pulmonary and central nervous system infections in immune-compromised patients. It is most recognized as a cause of morbidity and mortality in HIV patients and kills approximately 600,000 people annually with the majority of deaths in resource-limited regions with high HIV endemicity. One of the major medical issues for the treatment of C. neoformans is that the gold standard therapy of amphotericin B plus 5-flucytosine is not available in resource-limited regions where it is most desperately needed. The success of this therapy is due to its ability to directly kill the fungus in the CNS (fungicidal activity). The therapy most widely used in resource-limited regions is fluconazole, which is a fungistatic agent which, although it does directly kill Cryptococcus to a limited extent, is associated with poorer outcomes as well the emergence of drug-resistant organisms. Consequently, new agents are needed for the treatment of this pathogen.
Only one new class of antifungal agents has been developed in the last twenty years (i.e. echinocandins) and it does not have clinically useful activity against C. neoformans. The echinocandins inhibit the synthesis of 1,3-β-glucan, the key structural component of fungus cell walls. Since the cell wall is unique to fungi with no analog in humans, it is a very attractive antifungal drug target. Despite the fact that C. neoformans synthesizes 1,3-β-glucan, the organism is resistant to echinocandins and, to date, there are very few molecules with any activity toward cell wall processes in C. neoformans. Therefore, the identification of this new molecule that targets the C. neoformans cell wall not only provides a potential antifungal drug candidate but is also a useful mechanistic probe with which to study the unique cell wall biosynthesis machinery in this pathogen.