Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump

Abstract

Aim: In this study, we investigated the effect of plagiochin E (PLE), a botanic‐derived phenolic natural product, on reversal of fungal resistance to fluconazole (FLC) in vitro and the related mechanism. Methods and Results: A synergistic action of PLE and FLC was observed in the FLC‐resistant Candida albicans strains and was evaluated using the fractional inhibited concentration index. The effect of PLE on FLC intracellular uptake was investigated in FLC‐resistant C. albicans cells by liquid chromatography–tandem mass spectrometry, and the effect on efflux drug pump was assessed by measuring the efflux of Rhodamine 123 (Rh123). PLE significantly inhibited the efflux, but not the absorption, of Rh123 in FLC‐resistant strains in phosphate‐buffered saline with 5% glucose. Overexpression of the multidrug‐resistance gene CDR1 in FLC‐resistant C. albicans isolates was detected, and the introduction of PLE to the cells showed a significant reduction of the CDR1 expression in those FLC‐resistant isolates. Conclusions: These findings indicate that PLE could reverse the fungal resistant to FLC by inhibiting the efflux of FLC from C. albicans, and this effect may be related to the efflux pump. Significance and Impact of the Study: These results indicate that the combination of PLE and FLC may provide an approach for the clinical therapy of fungus infection induced by FLC‐resistant strains.

The Effect of Plagiochin E Alone and in Combination with Fluconazole on the Ergosterol Biosynthesis of Candida albicans

“…It has been reported that PLE increased the intracellular accumulation of FLC in C. albicans by inhibiting its efflux by the MDR protein on the cell membrane. 9) In this study, when FLC-resistant strain was treated by PLE, the decreases in the content of 14a-methylfecosterol and the downregulation of ERG11 may indicate the other mechanism for resistance reverse. Resistance to FLC and other azole is the result of a combination of different molecular mechanisms, and the reversing the resistance of C. albicans against FLC may also work by different combination of mechanisms with relative differences in potency.…”

“…CDR1-mediated drug resistance was susceptible to changes in membrane fluidity. 17,18) Our initial investigations showed that PLE can obviously reduce the expression of CDR1, 9) which may be influenced by imbalances in membrane lipid composition.…”

“…Synergistic effects between PLE and FLC were also observed on FLC-resistant strains by the combination of PLE and FLC. 8,9) Some PLE analogues demonstrated the antifungal activities through inhibiting the synthesis of ergosterol. 10,11) These findings stimulated our interest in determining whether PLE also targets the ergosterol biosynthetic pathway.…”

Secondary Metabolites in Bryophytes: An Ecological Aspect

“…From an ecological point of view, macrocyclic bis(bibenzyls) may also play an important role in sensitizing the resistant pathogenic fungi by promoting the permeability of antimicrobial agents and inhibiting efflux pumps on fungal cell membrane, although the descriptions are only limited to common clinical pathogenic fungus C. albicans [32]. Therefore, macrocyclic bis(bibenzyls) were used for the control of microbial infections and the reversal of the developing antibiotic resistance in bryophytes.…”

The Inhibitory Effect of a Macrocyclic Bisbibenzyl Riccardin D on the Biofilms of <i>Candida albicans</i>

“…11,12) Bisbibenzyl compounds, exclusively occurred in liverworts 13) have proven to be very effective against different clinically important fungi, and it is also active against those Candida isolates displaying high levels of fluconazole resistance. 14,15) In this study, we demonstrate the inhibitory effect of riccardin D (Fig. 1), an macrocyclic bisbibenzyl isolated from Chinese liverwort Dumortiera hirsute, 16) on the biofilm formation of C. albicans through downregulating the expression level of hyphae related genes and inhibiting the formation of hyphae.…”