On the mode of anti-C. albicans activity of a bis(benzoxaborole) analogue of tavaborole.

BACKGROUND

Benzoxaboroles showed significant antimicrobial efficacy in the past, warranting further investigation.

RESEARCH DESIGN AND

METHODS

Benzoxaboroles were evaluated for their cytotoxicity on Vero E6 and PBMCs, as well as their embryotoxicity in zebrafish embryos. Benzoxaboroles' impact on C. albicans in planktonic and biofilm was assessed. Advanced microscopy provided insights into C. albicans viability, while RNA-seq identified differentially expressed genes, with docking studies underscoring the potential of benzoxaboroles against fungi.

RESULTS

Bis(benzoxazole) analog (2) and Tavaborole effectively inhibited C. albicans, decreasing viability to 80% at 64 µg/mL compared to 60% at 16 µg/mL. The biofilm-inhibiting concentration (BIC50) was 2 μg/mL, leading to a 50% reduction in biofilm activity. 2 exhibited limited morphogenesis, it displayed significantly lower embryotoxicity compared to Tavaborole, with an IC50 greater than 128 μg/mL. 2 maintained approximately 80% viability of VERO E6 at 64 μg/mL. 2 reported an IC50 of 2 μg/mL against PBMCs. RNA-seq revealed upregulation of efflux pumps (MDR) and downregulation of inositol-1-phosphate synthase during benzoxazole treatment. Docking studies confirmed interactions with LeuRS.

CONCLUSIONS

Benzoxaboroles exhibited a similar resistance to azoles, which is associated with increased MDR1 and IDH6 levels. Efflux inhibitors for benzoxaboroles were crucial for treating candidiasis and may inspire future antifungal research.