Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1

• Published in: BMC complementary and alternative medicine Vol. 22; no. 1; pp. 1 - 264
• Main Authors: Gil, Florimar, Laiolo, Jerónimo, Bayona-Pacheco, Brayan, Cannon, Richard D, Ferreira-Pereira, Antonio, Carpinella, María Cecilia
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 12-10-2022; BioMed Central; BMC
• Subjects: ABC transporters; Accumulation; Antifungal activity; Antifungal agents; Biological products; Candida; Candida albicans; Candida glabrata; Cdr1; Chemosensitization; Clinical isolates; Complementarity-determining region 1; Drug resistance; Drug resistance in microorganisms; Efflux; Efflux transporter; Ethanol; Fluconazole; Fungicides; Indigenous plants; Infections; Laboratories; Mdr1; MDR1 protein; Multidrug resistance; Multidrug resistant organisms; P-Glycoprotein; Pathogens; Plant extracts; Pumps; Yeasts; Argentina; United States > US
• ISSN: 2662-7671; 2662-7671; 1472-6882
• DOI: 10.1186/s12906-022-03745-4

Background The development of multidrug resistance (MDR) associated with the overexpression of the efflux transporters Mdr1 and Cdr1 in Candida species impedes antifungal therapies. The urgent need for novel agents able to inhibit the function of both pumps, led us to evaluate this property in 137 extracts obtained from Argentinian plants. Methods The ability of the extracts to reverse efflux pump-mediated MDR was determined with an agar chemosensitization assay using fluconazole (FCZ) resistant Mdr1- and Cdr1-overexpressing clinical isolates of Candida albicans and Candida glabrata as well as Saccharomyces cerevisiae strains selectively expressing Mdr1 (AD/CaMDR1) or Cdr1 (AD/CaCDR1). The resistance-reversing activity of the most potent extracts was further confirmed using a Nile Red accumulation assay. Results Fifteen plant extracts overcame the FCZ resistance of Candida albicans 1114, which overexpresses CaMdr1 and CaCdr1, and AD/CaMDR1, with those from Acalypha communis and Solanum atriplicifolium being the most effective showing 4- to 16-fold reversal of resistance at concentrations [greater than or equal to] 25 [micro]g/mL. Both extracts, and to a lesser extent that from Pterocaulon alopecuroides, also restored FCZ sensitivity in CgCdr1-overexpressing C. glabrata 109 and in AD/CaCDR1 with fold reversal values ranging from 4 to 32 and therefore demonstrating a dual effect against Mdr1 and Cdr1. Both, A. communis and S. atriplicifolium extracts at concentrations [greater than or equal to] 12.5 and [greater than or equal to] 25 [micro]g/mL, respectively, increased the intracellular Nile Red accumulation in all yeast strains overexpressing efflux pumps. Conclusions The non-toxic and highly active extracts from A. communis and S. atripicifolium, provide promising sources of compounds for potentiating the antifungal effect of FCZ by blocking the efflux function of Mdr1 and Cdr1 transporters. Keywords: Multidrug resistance, Efflux transporter, Mdr1, Cdr1, Candida albicans, Candida glabrata, Nakaseomyces glabrata, ATP binding cassette, Major facilitator superfamily