Anticandidal activity of L-β-(isoxazolin-5-on-2-yl)-alanine due to the inhibition of O -acetyl-L-homoserine sulfhydrylase and cystathionine γ-synthase

The L-β-(isoxazolin-5-on-2-yl)-alanine (BIA) exhibits in vitro growth inhibitory activity against human pathogenic yeasts of Candida spp, with MIC90 values in 0.5 – 8 µg/mL range. BIA is transported in Candida albicans by the Mup1p permease and then inhibits enzymes of the methionine biosynthetic pathway, O-acetyl-L-homoserine sulfhydrylase Met15p and cystathionine γ-synthase Str2p. The slight, borderline synergistic effect was observed for combination of BIA with L-penicillamine. BIA was found to be a competitive inhibitor of Met15p and Str2p, with Ki values equal to 0.711 mM and 0.912 mM, respectively. Results of the molecular docking analysis of BIA binding at Met15p active centre suggest that this compound could possibly act as a dead-end inhibitor. The same mechanism of Str2p inhibition by BIA is suggested. BIA is the first identified inhibitor of both Met15p and Str2p, exhibiting moderate growth inhibitory activity against human pathogenic yeasts of the Candida genus.