Tetrandrine enhances the antifungal activity of fluconazole in a murine model of disseminated candidiasis

Abstract

BackgroundTetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications as an anti-inflammatory or anti-arrhythmic agent in the treatment of diverse diseases. In our previous study, TET exhibited the synergisitic action on azoles against pathogenic fungi. PurposeIn the current study, we examined whether TET can enhance the antifungal activity of FLC against disseminated candidiasis in mice. MethodsBALB/c mice were inoculated intravenously with FLC-sensitive or FLC-resistant strains of Candida albicans, randomized and treated intraperitoneally with different doses of TET and/or FLC daily for 7 days. The treatment effectiveness, fungal burdens and the levels of the IFN-γ, IL-10, TGF-β1 and IL-17A are determined in serum by ELISA and in the kidney by Real-time RT-PCR methods. ResultsWe found that treatment with 45, 30 and 15 mg/kg of TET, enhanced the antifungal activities of a sub-critical dose (0.4 or 5 mg/kg) and minimal dose (0.8 or 10 mg/kg) of FLC against FLC-sensitive and FLC-resistant (respectively) infected mice. In the resistant strains the resistance mechanisms included MDR1 overexpression-and CDR1/CDR2 overexpression. Furthermore, when animals were treated with a sub-high dose (1.6–3.2 and 20–30 mg/kg) of FLC in the presence of fixed amounts of TET at 45, 30 and 15 mg/kg, the therapeutic doses of FLC could be substantially reduced in all strains tested. The findings in infected animal are consistent with the conclusion that TET exerts a synergistic effect on FLC against C. albicans by fractional inhibitory concentration index (FICI) and time-killing test in vitro. ConclusionIn summary, our data indicate that TET will enhance the antifungal activity of FLC against C. albicans infection in disseminated mice model.