Interactions of a prenylated flavonoid from Dalea elegans with fluconazole against azole- resistant Candida albicans

BARCELO S; PERALTA M; CALISE M,; FINCK, SOLEDAD; ORTEGA MG; DIEZ R.A.,; CABRERA J; PEREZ CRISTINA

PHYTOMEDICINE

ELSEVIER GMBH

Año: 2017

0944-7113

Backgound: The prenylated flavonoid 2?, 4?-dihydroxy-5?-(1???, 1???-dimethylallyl)-8-prenylpinocembrin (8PP, formerly 6PP) shows antifungal activity, inhibits rhodamine 6G efflux and reverses fluconazole (FCZ)resistance in azole-resistant Candida albicans overexpressing cdr1, cdr2 and mdr1 transporters.Purpose and design: In this paper, we tried to characterize 8PP in vitro interactions on the cell growth and lethality of C. albicans. We also initiated preliminary in vivo toxicological studies on mice.Methods: The effects of 8PP and FCZ on cell growth and viability of C. albicans were evaluated by CLSI standards. The checkerboard assay was used to search for interactions on cell growth. The time-kill assay was used to study fungicidal effects. Acute toxicity was evaluated at a single dose schedules.Results: From the checkerboard design, and using a starting inoculum of 103 CFU/ml, the fractional inhibitory concentration (FIC) of FCZ and 8PP could be determined as 0.11 and 0.50, respectively, with a FIC index value (FICI) of 0.61. This FICI and the isobologram showing a concave shapesuggests an additive interaction between them. At a higher starting inoculum (105 CFU/ml), C. albicans growth and viability were decreased by FCZ,8PP and their combination in a concentration-dependent way. For FCZ, minimum fungicidal concentration (MFC) and FC50 (the concentration that kills 50% of the fungal cells) were 4-fold reduced (280 to 70 μM) in combination with 125 μM 8PP. A decrease of 3 log units in viable counts with respect to control was reached (3.65 ±1.05 ?, p