<i>Enterococcus faecalis</i> bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of <i>Candida albicans</i>.

Abstract

<i>Enterococcus faecalis</i>, a Gram-positive bacterium, and <i>Candida albicans</i>, a fungus, occupy overlapping niches as ubiquitous constituents of the gastrointestinal and oral microbiome. Both species also are among the most important and problematic, opportunistic nosocomial pathogens. Surprisingly, these two species antagonize each other's virulence in both nematode infection and in vitro biofilm models. We report here the identification of the <i>E. faecalis</i> bacteriocin, EntV, produced from the <i>entV</i> (<i>ef1097</i>) locus, as both necessary and sufficient for the reduction of <i>C. albicans</i> virulence and biofilm formation through the inhibition of hyphal formation, a critical virulence trait. A synthetic version of the mature 68-aa peptide potently blocks biofilm development on solid substrates in multiple media conditions and disrupts preformed biofilms, which are resistant to current antifungal agents. EntV⁶⁸ is protective in three fungal infection models at nanomolar or lower concentrations. First, nematodes treated with the peptide at 0.1 nM are completely resistant to killing by <i>C. albicans</i> The peptide also protects macrophages and augments their antifungal activity. Finally, EntV⁶⁸ reduces epithelial invasion, inflammation, and fungal burden in a murine model of oropharyngeal candidiasis. In all three models, the peptide greatly reduces the number of fungal cells present in the hyphal form. Despite these profound effects, EntV⁶⁸ has no effect on <i>C. albicans</i> viability, even in the presence of significant host-mimicking stresses. These findings demonstrate that EntV has potential as an antifungal agent that targets virulence rather than viability.