Grant: Operating Grant

The fungus Candida albicans is one of the most commonly encountered human pathogens. It causes a wide variety of infections, ranging from mucosal infections in healthy individuals (oral thrush, vaginitis) to life-threatening systemic infections in individuals with an impaired immune system (candidemia). The drugs most widely used for the treatment of these infections are azoles. However, treatment failure due to the emergence of azole-resistant strains of C. albicans in patients receiving long-term therapy, such as AIDS patients, is an important medical problem. During the past funding period of this project by CIHR, we have found that many azole-resistant C. albicans clinical isolates overexpress the PDR16 gene. This gene produces a protein whose predicted function is to transfer specific lipids (phospholipids) between different sub-compartments of the cell. We have also shown that deleting this gene from azole-resistant C. albicans cells significantly decreases their resistance to azole drugs, by an unknown mechanism. Finally, we have shown that PDR16 overexpression in azole-resistant clinical isolates is due to mutations in a protein called TAC1. This protein is a transcription factor whose role is to control the expression of genes into proteins (for example, the PDR16 gene). Our proposed research project uses genetic, genomic, molecular biology and biochemical approaches and is aimed at better understanding the function of these proteins in the response of C. albicans cells to azole drugs. The results from our studies will help to better understand the molecular mechanisms of azole resistance, with the aim of circumventing or preventing it. Our studies will also contribute to a better knowledge of the biology of this as well as other medically important fungi.