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The role of selective proteolysis in antifungal resistance

Tumour cells in culture often become resistant to drugs that were initially toxic to the cells. Remarkably, the development of resistance to one drug also makes the cell less sensitive to a variety of other unrelated compounds. This phenomenon is known as multiple drug resistance. Increased tolerance to azole compounds in yeast was found to correlate with the overexpression of a membrane ABC-transporter protein acting as a drug efflux pump. Ubiquitin-mediated proteolysis is a cellular process for maintaining normal protein levels. Our research aims at understanding the molecular mechanisms that target the yeast Pdr5 ABC-transporter for selective proteolysis. In particular, we focus on the proteins addressing Pdr5 into two distinct proteolytic pathways and on the Pdr5 sequences responsible for the recognition.

Baker’s yeast as a model organism for studying multidrug resistance

Baker’s yeast Saccharomyces cerevisiae and the closely related fungal pathogen Candida albicans are simple eukaryotic organisms but multiple drug resistance is mediated by the same type of transporter proteins in the yeasts and humans. The ease of mutant isolation and the existence of well-defined genetic and biochemical approaches made S. cerevisae a suitable organism for deciphering the connection of genes and proteins with the functions that they provide to cells.

Targeting Pdr5 for degradation as a strategy to fight multidrug–resistant infection

Overexpression of the long-lived Pdr5 protein leads to increased azole resistance. We have shown that a newly synthesised protein that fails to fold into a functional pump is eliminated by the proteasome. We have also found that the localisation at the cell surface requires post-translational modifications. In their absence, Pdr5 is addressed to the vacuole for degradation. A better understanding of the underlying mechanisms is necessary to test the possibility of increased Pdr5 degradation as a tool to treat fungal infections.