Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis

Candida glabrata has emerged
as
an important opportunistic pathogen of invasive candidiasis due to
increasing drug resistance. Targeting Pdr1-KIX interactions with small
molecules represents a potential strategy for treating drug-resistant
candidiasis. However, effective Pdr1-KIX inhibitors are rather limited,
hindering the validation of target druggability. Here, new Pdr1-KIX
inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent
KIX binding affinity, leading to enhanced synergistic efficacy with
fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting
the efflux pump and down-regulating resistance-associated genes through
blocking the Pdr1-KIX interaction. Compound B8 exhibited
excellent in vitro and in vivo antifungal
potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect
to treat C. glabrata infection, suggesting
new mechanisms of action independent of Pdr1-KIX inhibition. Therefore,
compound B8 represents a promising lead compound for
antifungal drug development.