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

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).

Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

“…Although the screens denoted low/medium throughput may have investigated large numbers of compounds, high-throughput screens (HTS) are defined by a significant degree of automation. Both low-and high-throughput screens have included use of C. albicans strains known to overexpress efflux pumps [53,60] or recombinant S. cerevisiae strains hyperexpressing a specific efflux pump from a pathogenic fungus [35,54,55,[61][62][63]. The compound libraries used are varied, but are either large-scale collections of small molecules such as the Molecular Libraries Small Molecule Repository (MLSMR) established by the NIH [64], collections of known drugs such as the Prestwick chemical library [65], collections of natural products and/or extracts [61,[66][67][68][69][70][71], or are members of a family of compounds targeted to a structure of i nterest, such as a cell surface-targeted peptide library [35].…”

“…Screens have identified a number of fungal efflux pump inhibitors (Table 1 & Figure 2). Inhibitors identified include isonitrile [71], FK506 [56], enniatins [68], beauvericin [84], milbemycins [69], sulphated sterols [66], capisterones [61], derivatives of cerulenin [53], chalcones [60] and phenothiazine [73,86], ibuprofen [87], farnesol [88], a synthetic peptide [35], compounds with a squarile core [55] and the out-of-patent drug clorgyline [54]. Five of the compounds (RC21v3 [35]; clorgyline [54]; squarile core compounds [55]; beauvericin and unnarmicins [84,89]) were discovered using the heterologous S. cerevisiae AD/pABC3 expression system [56].…”

High-throughput fluorescence screening assay for the identification and comparison of antimicrobial peptides’ activity on various yeast species

“…Alternatively, microscopic examination of fluorescent dye uptake or measurement of the leakage of intracellular constituents can reveal the type of cell damage generated by the drug (Lee and Lee, 2015). A fluorescence assay based on the potential-dependent redistribution of the fluorescence probe diS-C3(3) (3,3'-dipropylthiacarbocyanine iodide) has been gradually developed and successfully used to identify the mechanism of action of a wide range of drugs for several years (Chládková et al, 2004;Hendrych et al, 2009;Kodedová et al, 2011;Łącka et al, 2015). The principles of diS-C3(3) assays and application of this fluorescence method in studies of the effects of antifungal compounds on Saccharomyces cerevisiae were described in detail in our former work (Kodedová et al, 2011).…”

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole

“…Inhibition of the pump ATPase activity is, however, not the only mechanism blocking CaCdr1p-mediated fluconazole transport. There are molecules that reverse fluconazole resistance mediated by CaCdr1p without affecting its pump ATPase activity (e.g., chalcone derivatives [18], farnesol [36], and curcumin [20]). Although we cannot say how these compounds inhibit C. albicans Cdr1p and Mdr1p, it is certain that some of the organotellurium compounds 1 to 5 could chemosensitize C. albicans-resistant isolates to fluconazole.…”

“…Many compounds, including FK506 (16), unnarmicins A and C (17), chalcone derivatives (18), disulfiram (19), curcumin (20), ibuprofen (21), and some promising milbemycins (22,23), are capable of restoring the fluconazole susceptibility of C. albicans-and C. glabrataresistant isolates, as well as the innately fluconazole-resistant C. krusei. However, fewer compounds have been described to reverse fluconazole resistance of Mdr1p-overexpressing clinical isolates.…”