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

Background: Tetrandrine (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-ar-rhythmic agent in the treatment of diverse diseases. In our previous study, TET exhibited the synergisitic action on azoles against pathogenic fungi. Purpose: In the current study, we examined whether TET can enhance the antifungal activity of FLC against disseminated candidiasis in mice. Methods: BALB/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-gamma, IL-10, TGF-beta and IL-17A are determined in serum by ELISA and in the kidney by Real-time RT-PCR methods. Results: We 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. Conclusion: In summary, our data indicate that TET will enhance the antifungal activity of FLC against C. albicans infection in disseminated mice model.