Efflux Pumps in clinical drug resistance

Over-expression of human P-glycoprotein (P-gp) remains the most documented example of an ABC drug transporter responsible for the failure of chemotherapy in tumour cells. The presence of proteins homologous to P-gp in all other organisms ranging from prokaryotes to eukaryotes suggests that extrusion of drugs is a general mechanism of multidrug resistance. It is well-known that the enhanced expression of Cdr1 protein, a homologue of human P-gp, in azole resistant (AR) clinical isolates of the opportunistic human fungal pathogen Candida albicans leads to reduced accumulation of therapeutic azoles, which facilitates its survival.

Considering the importance of Cdr1 protein as major antifungal transport and the fact that it has novel mechanism of ATP hydrolysis and drug transport which is unique to all fungal transporters, our main objective is to understand the structure and function of Cdr1p to design inhibitors/modulators to jam the pump protein activity so the drug already in use could again sensitize resistant Candida cells., An understanding of the mechanism underlying MDR in order to identify new antifungal targets at the level of transcriptional regulation represent another alternate strategy being pursued.