Functionally Relevant Residues of Cdr1p: A Multidrug ABC Transporter of Human Pathogenic Candida albicans

Reduced intracellular accumulation of drugs (due to rapid efflux) mediated by the efflux pump proteins belonging to ABC (ATP Binding Cassette) and MFS (Major Facilitators) superfamily is one of the most common strategies adopted by multidrug resistance (MDR) pathogenic yeasts. To combat MDR, it is essential to understand the structure and function of these transporters so that inhibitors/modulators to these can be developed. The sequence alignments of the ABC transporters reveal selective divergence within much conserved domains of Nucleotide-Binding Domains (NBDs) which is unique to all fungal transporters. Recently, the role of conserved but divergent residues of Candida Drug Resistance 1 (CDR1), an ABC drug transporter of human pathogenic Candida albicans, has been examined with regard to ATP binding and hydrolysis. In this paper, we focus on some of the recent advances on the relevance of divergent and conserved amino acids of CaCdr1p and also discuss as to how drug interacts with Trans Membrane Domains (TMDs) residues for its extrusion from MDR cells. 1. Introduction The pathogenic Candida albicans accounts for approximately 50–60% causes of candidiasis particularly in immuno-compromised human patients. But the infections caused by non-albicans species, such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei are also common particularly in neutropenic patients and neonates [1–4]. Of note, recently, the incidences of albicans and non-albicans species of Candida acquiring resistance to antifungals (particularly to azoles) have increased considerably which poses problems towards its successful chemotherapy [5–7]. On one hand, to combat antifungal resistance, search for better drugs with newer targets is underway; on the other hand, Candida cells have evolved a variety of strategies to develop resistance to common antifungals. The main mechanisms of antifungal resistance to azoles include alterations in ergosterol biosynthetic pathway by an overexpression of ERG11 gene which encodes the drug target enzyme 14∝-demethylase or by an alteration in target enzymes (point mutations) [3, 8, 9]. Reduced intracellular accumulation of drugs (due to rapid efflux) is another prominent mechanism of resistance in Candida cells [10]. Most commonly, genes encoding drug efflux pumps belonging to ABC (ATP binding cassette) and MFS (Major Facilitator) superfamilies of proteins are overexpressed in azole resistant Candida isolates which abrogates intracellular accumulation leading to enhanced tolerance to drugs (Figures 1(a) and 1(b)). Figure 1: A cartoon