Synergistic and drug-resistant reversing effects of diorcinol D combined with fluconazole against Candida albicans

The emergence of drug resistance and limitation of antifungal agents bring enormous challenges to the management of Candida infection. Combination therapy is a useful way to treat the fungal infection, especially for those difficult-to-treat infections. In this research, we investigated the interaction effects between diorcinol D (DD), an antifungal active natural product from lichen endophytic fungus and fluconazole (FLC) against planktonic cells and mature biofilms of Candida albicans in vitro by checkerboard microdilution and time-killing tests. Both fractional inhibitory concentration index model and ΔE model revealed a synergistic antifungal action between DD and FLC against all five azole-resistant isolates and synergistic or indifferent effects for other five azole-sensitive isolates. In addition, the synergies were obtained from eradicating C. albicans mature biofilms tests using two wild-type strains (SC5314 and YEM30), an azole-resistant isolate 28I and an azole-sensitive isolate 18B. The time-killing tests also showed synergistic fungicidal action between DD and FLC. Mechanism test revealed that DD inhibited the activity of efflux pump and retarded the biosynthesis of ergosterol, which probably contributed to the synergetic action as well as the reversing activity of drug resistance.