Analysis of Antimicrobial Resistance in Candida Albicans Using Modulators of MDR/CDR Gene Expression

Abstract

Majority of life-threatening fungal infections in clinics are caused by Candida albicans. The emergence of azole resistance in fungi complicates patient management. In response to chemical stress, C. albicans make transient changes in the gene expression for survival. Notable among these is the upregulation of efflux pump which is known to be the main mechanism of antifungal resistance. Potent therapeutic agents targeting this resistance mechanism are urgently needed. Chemo-sensitization is postulated as one way to overcome antifungal resistance. Endophytic fungi produce bioactive metabolites which are used as chemotherapeutic agents. The aim of this study is to use modulators of CDR and MDRs genes as probes to study chemo-sensitization and resistance phenotypes. Also, fungal metabolites (alone and in combination with chemosensitizers) will be used to reverse antifungal resistance. On analysis of phenotypic switching of the fungal cells in the presence of efflux modulators and phenotypic modifiers, S. cerevisiae was frequently observed to switch phenotypes as compared to C. albicans. Chemical compounds, including, compounds PC04-10, PC04-11, PC04-16 and PC04-23, significantly modified the antimicrobial phenotypes of Candida albicans and Saccharomyces cerevisiae and could be considered for use as synergistic partners of antifungal drugs to overcome resistance. Also, it was realized that some compounds including rifampicin, estradiol, PC04-09 and PC04-14 caused resistance. A total of 40 out of 507 bioactive and 90 chemosensitizing extracts were identified from SBF and TEF fungal extracts. In the Rhodamine efflux assay, six compounds were found to inhibit S. cerevisiae efflux, these well trifluoperazine, trifluoprozerazine, thioridazine, chlorpromazine, deferasirox and ibuprofen, whereas in C. albicans only the last four out of the six compounds were active. Also, 13 out of 20 chemosensitizing extracts significantly inhibited efflux activity of C. albicans and S. cerevisiae. Thus, fungi are good sources of novel and potent antifungal and chemosensitizing compounds.