Mechanism of berberine-mediated fluconazole-susceptibility enhancement in clinical fluconazole-resistant Candida tropicalis isolates

Candida tropicalis was one of the most common non-albicans Candida (NACA) species creating relatively high morbidity and mortality. We previously demonstrated that the antifungal effect of BBR in combination with FLC might be attributed to reactive oxygen species production, ergosterol content and efflux pump levels in a clinical C. tropicalis isolate. we employed thirteen clinical C. tropicalis isolates as well as four standard reference strains to evaluate the antifungal activity of BBR in combination with FLC under planktonic and biofilm states by analyzing the mRNA expressions of ERG11, CDR1 and MDR1 by qRT-PCR. The susceptibility tests showed that BBR in combination with FLC produced a FICI range of 0.13-1 under planktonic state and 0.25–1 under biofilm state in the seventeen strains. The mRNA expressions of ERG11, CDR1 and MDR1 were upregulated 1.43–2.10 and 1.47–4.42 fold in the case of BBR/FLC used alone compared with the control. The combined usage of BBR plus FLC resulted in a decrease of 2.84- (p < 0.01) and 2.39-fold (p < 0.05) in the expression of ERG11 mRNA, 2.98- (p < 0.05) and 3.06-fold (p < 0.05) in the expression of CDR1 mRNA, 1.41- and 4.33-fold in the expression of MDR1 mRNA compared with the BBR/FLC used alone. The synergism of BBR with FLC might be relevant with the inhibitions on the mRNA expressions of ERG11 and efflux pumps.