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

Abstract

AbstractWe presented the pharmacodynamic relationship between benzoxaborole concentrations andCandida albiansblastoconidial population dynamics. Bis(benzoxaborole) analogue (2) andTavaborole(ref.) showed comparable moderate effects againstC. albicans(time-kill kinetic assays). Benzoxaboroles inhibited theC. albicansgrowth during 72 h (fungicidal after 2 h of that time) with metabolic reduction (%R=64). Biofilm-inhibiting concentration (BIC50=2 μg/mL) is the lowest concentration of bezoxaboroles that presented 50% inhibition of biofilm metabolic activity vs non-treated control.2displayed poor ability to inhibit morphogenesis ofC. albicans. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish modelin vivo. This biofilm model was used to study the interactions between theC. albicansmorphogenesis and benzoxaboroles. Benzoxaboroles displayed selectivity in cytotoxic effects.2exhibited significantly lower embryotoxicity vs ref. IC50>128 μg/mL for2. Ref. at 256 μg/mL 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. and2showed IC50=2 μg/mL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) inC. albicanswere upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment.MDR1upregulation by2was accompanied by theIFD6(aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression ofMDR1andIDF6. 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.