Cryptococcal meningitis is one of the most dangerous fungal infections caused by Cryptococcus neoformans. Immunocompromised individuals are susceptible to fungal infections and annually, 1.1 million incidences of cryptococcal meningitis infections are recorded with deaths reaching 18000 globally. Current treatments use antifungals, but they are toxic, costly and variable in their effects, resulting in the need for frequent hospitalization, and drug resistance. Therefore, pioneering a treatment that is more affordable and effective is a rising urgent need. The purine metabolic pathway has been the target for drug design as it is composed of a series of processes involved with ATP and GTP synthesis, which is essential as an energy source for cellular functions. Previous studies from our laboratory supports that enzymes in this pathway can serve as potential antifungal targets.
5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is one of the enzymes in this pathway that was chosen for study to determine its potential as an antifungal. ADE16, which encodes ATIC was deleted from C. neoformans genome which is shown to be an adenine and histidine auxotroph.
As a first step, characterisation of AICAR transformylase/IMP cyclohydrolase from C. neoformans was performed using various biochemical and structural biology techniques,
Crystals of ATIC were cryoprotected and data was collected at the Australian Synchrotron. The structure of C. neoformans ATIC was solved to 2.7Ǻ., which shown subtle differences to be exploited for drug design.