Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives.

Izabela Ła̧Cka,Anita Bułakowska,Marek T Konieczny,Marie Kodedová,Dana Gašková,Sławomir Milewski,Rajendra Prasad,Indresh K Maurya

doi:10.3389/fmicb.2015.00783

Abstract

Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux pumps. The observed effect of sensitization of resistant strains of Candida albicans to fluconazole activity in the presence of active compounds most likely resulted from inhibition of the pump-mediated efflux, as was revealed by the results of studies involving the fluorescent probes, Nile Red, Rhodamine 6G and diS-C3(3).

Highlights

Opportunistic fungal infections in immunocompromised hosts have become an important clinical problem, with Candida species remaining one of the leading causes of hospital-acquired bloodstream infections
Three out of 27 chalcones studied in this work (Figure 4) appeared effective chemosensitizers, able to restore to large extent sensitivity to fluconazole of multidrug resistance (MDR) C. albicans strains
This is worth mentioning that compounds 6, 18, and 21 demonstrated low in vitro mammalian toxicity against different cell lines in the tissue cultures (Konieczny et al, 2007a,b,c), what makes them promising candidates for clinical application as agents augmenting antifungal chemotherapy with FLC of infections caused by MDR C. albicans

Summary

Introduction

Opportunistic fungal infections in immunocompromised hosts have become an important clinical problem, with Candida species remaining one of the leading causes of hospital-acquired bloodstream infections. The attributable frequency of deaths from candidemia remains close to 40% and Candida albicans comprises nearly half of the isolated fungal pathogens (Pfaller and Diekema, 2007). A number of efflux pumps have been identified in fungi, including Cdr1p, Cdr2p, Mdr1p, and Flu1p in C. albicans (Prasad et al, 2002; Prasad and Goffeau, 2012). In view of these facts, the search for new antimycotics active against MDR fungi and/or chemosensitizers, i.e., compounds able to render MDR strains sensitive to clinically used antifungals, is an urgent need. Reported examples of compounds effectively chemosensitizing FLC-resistant human pathogenic

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Conclusion