Mitigating Candida albicans virulence by targeted relay of pulcherriminic acid during antagonistic biofilm formation by Bacillus subtilis

Abstract

The antagonistic biofilms formed by probiotic Bacilli may significantly mitigate persistent strains of Candida albicans, which are often involved in severe oral, vulvovaginal or systemic infections in humans. Here, we report on a spatiotemporal antagonistic activity mediated through pulcherriminic acid (PA) production by biofilm-forming B. subtilis, which is subsequently transported to the extracellular environment and binds ferric iron to form red-coloured pigment pulcherrimin. We show that the pulcherrimin building-up is targeted towards the C. albicans macrocolony via B. subtilis biofilm branching and successive PA relay. Furthermore, biofilm-forming B. subtilis cells demonstrate robust hyphal colonization that results subsequent eradication of C. albicans. Besides, extracted pulcherrimin mitigates C. albicans biofilm formation and yeast-to-hyphae (Y–H) transition. We further find that the mode of hyphal colonization could be regulated via SpoA-SinI pathway, while pulcherrimin relay is connected to surfactin production machinery. We assume therefore that the pulcherrimin relay for iron hijacking, in parallel to the direct hyphal colonization by biofilm-forming Bacilli, may provide a promising platform for developing therapeutic concepts to overcome antibiotic persistence in pathogenic yeasts.