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Abstract
The frequent emergence of azole-resistant strains has increasingly led azoles to fail in treating candidiasis. Combination with other drugs is a good option to effectively reduce or retard its incidence of resistance. Natural products are a promising synergist source to assist azoles in treating resistant candidiasis. Eucalyptal D (ED), a formyl-phloroglucinol meroterpenoid, is one of the natural synergists, which could significantly enhance the anticandidal activity of fluconazole (FLC) in treating FLC resistant C. albicans. The checkerboard microdilution assay showed their synergistic effect. The agar disk diffusion test illustrated the key role of ED in synergy. The rhodamine 6G (R6G) efflux assay reflected ED could reduce drug efflux, but quantitative reverse transcription PCR analysis revealed the upregulation of CDR1 and CDR2 genes in ED treating group. Efflux pump-deficient strains were hyper-susceptible to ED, thus ED was speculated to be the substrate of efflux pump Cdr1p and Cdr2p to competitively inhibit the excretion of FLC or R6G, which mainly contributed to its synergistic effect.
Highlights
Candidiasis is the most frequently encountered fungal infection
All strains were routinely stored at −80◦C in yeast-peptonedextrose medium (YPD; 1% yeast extract, 2% peptone, and 2% dextrose), supplemented with 20% glycerol and were subcultured on YPD plates twice at 35◦C before each experiment
Eucalyptal D (ED) was active against FLC susceptible strains with minimum inhibitory concentrations (MIC) value lower than 64 μg/ml, it didn’t exhibit evident effects against FLC resistant isolates under the concentration of 128 μg/ml
Summary
Recent years have seen its steadily increasing incidence and mortality with risk factors continually emerging (Gamarra et al, 2010; Ruhnke, 2014; Tsai et al, 2015; Li et al, 2016) The azoles such as fluconazole (FLC), itraconazole (ICZ) and ketoconazole (KCZ) are widely and frequently used in clinic to fight candidiasis due to their high efficiency and low toxicity (Marchetti et al, 2003; Prasad and Rawal, 2014; Shrestha et al, 2015; Lu et al, 2017). One of them is the increase of membrane transporters, such as Cdr1p, Cdr2p, and Mdr1p, which can significantly increase drug efflux to allow tolerable intracellular drug concentration for Candida spp Another important factor is the overexpression or point mutation of ERG11 gene, which can alter the affinity of azoles with target enzyme lanosterol 14-demethylase (Luna-Tapia et al, 2015).
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