Exploring the Role of General Amino Acid Permeases in Candida albicans Sensitivity to the Calcineurin Inhibitor Drug FK506

With the rise of antifungal drug resistance there is a growing need for new treatments to become available. One current treatment avenue being considered is to repurpose calcineurin inhibitors as pan-fungal drugs. Unfortunately, it is already known that fungi can also develop resistance to this drug. It is therefore important that we ascertain which parts of the calcineurin signaling pathway play a role in this resistance; however, not all the components have yet been identified in fungi. Previous work in the fungal pathogen Mucor circinelloides revealed that many FK506-resistant isolates had mutations in one general amino acid permease (GAP) encoding gene, revealing a key role for this protein in the sensitivity pathway. Moreover, a potential role for GAPs has also been seen in the fungus Cryptococcus neoformans. Our goal was to determine whether a similar circuit exists in the much more clinically prevalent species Candida albicans which could then be targeted in a pan-fungal treatment. Through examination of modified strains either deleted for, or over-expressing, various GAP genes, we have shown that in C. albicans (i) there is functional redundancy among the GAPs and (ii) Gap 5 plays a role in FK506 sensitivity when overexpressed, while Gap 1 does not. Moreover, we have established that this signaling pathway functions independently of the transcription factor Crz1 – similar to the situation in M. circinelloides – providing reassurance that there are enough commonalities among the fungal species that a broad spectrum therapeutic could be developed.