Shweta Nim
Amity Institute of Integrative Sciences and Health, India
Title: Functional insight into the promiscuous role of multidrug transporters of Candida albicans
Biography
Biography: Shweta Nim
Abstract
Among the 28 putative ABC transporters and 95 putative MFS transporters identified in the C. albicans genome, only CaCdr1p and CaCdr2p and the MFS transporter CaMdr1p are major determinants of azole resistance and variety of structurally unrelated compounds such as lipids and steroids. The architecture of the drug-binding sites and promiscuity towards substrates is essential to understand the drug-protein interaction and provide a platform for rational design of modulators/inhibitors. Also the reversal of azole resistance is considered an attractive strategy to desensitize the multidrug resistant clinical isolates of C. albicans. Therefore, we have explored the poly-specific nature of the Cdr1 protein by screening its in-house mutant library with varied range of chemically related and unrelated compounds. Based on the biochemical mapping of essential residues, we established the substrate specificity of Cdr1p to be independent of size, charge and hydrophobicity. Our study also established the molecular basis of interaction of an immunosuppresant FK520 with Cdr1p and deduced the role of critical amino acids of the transporter protein, which if replaced with alanine, not only abrogated FK520-dependent competitive inhibition of drug efflux but simultaneously decreased susceptibility to azoles. Another class of compounds, macrocyclic diterpenes derived from Euphorbia species, reported as strong modulators of the transport activity of the human P-glycoprotein where found to inhibit drug-efflux activity and render fluconazole sensitization to CaCdr1p and CaMdr1p which may constitute valuable leads for developing effective modulators of C. albicans multidrug transporters.