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

Benzoxaboroles displayed selectivity in cytotoxic effects. 2 exhibited significantly lower embryotoxicity vs ref. IC50>128 μgmL for 2. Ref. at 256 μgmL showed approximately 80% viability of VERO E6 cells.

A higher selectivity of the ref—drug to the pathogen than to the mammalian cells was observed. Contrariwise, ref. and 2 showed IC50=2 μgmL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding.

RNAseq data indicated that efflux pumps (MDR) in C. albicans were upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment. MDR1 upregulation by 2 was accompanied by the IFD6 (aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1 encoding putative nicotinic acid transporter).

Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression of MDR1 and IDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. Moreover, C5_04480C_A (cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress.

Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Our findings present an innovative concept that can inspire further studies for designing and building new antifungal benzoxaborole.