摘要

粪肠球菌（一种革兰氏阳性菌）和白色念珠菌（一种真菌）作为胃肠道和口腔微生物组中普遍存在的成分占据重叠的生态位。这两种物种也是最重要和有问题的机会性医院感染病原体。令人惊讶的是，这两种物种在线虫感染和体外生物膜模型中都会对抗彼此的毒力。我们在这里报告从entV（ef1097）基因座产生的粪肠球菌细菌素EntV的鉴定对于通过抑制菌丝形成而降低白色念珠菌毒力和生物膜形成是必要和充分的，所述菌丝形成是关键毒力特征。合成形式的成熟68-aa肽在多种培养基条件下强力阻断固体基质上的生物膜发育并破坏对当前抗真菌剂有抗性的预形成生物膜。 EntV68在纳摩尔或更低浓度的三种真菌感染模型中是保护性的。首先，用肽以0.1nM处理的线虫完全抵抗白色念珠菌杀死。该肽还保护巨噬细胞并增强其抗真菌活性。最后，EntV68降低了口咽念珠菌病小鼠模型中的上皮侵袭，炎症和真菌负荷。在所有三种模型中，肽大大减少了菌丝形式存在的真菌细胞的数量。尽管有这些深远的影响，但EntV68对白色念珠菌的生存力没有影响，即使存在显着的宿主模拟应激。这些发现证明EntV具有作为抗真菌剂的潜力，其靶向毒力而不是生存力。

Enterococcus faecalis, a Gram-positive bacterium, and Candida albicans, 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 E. faecalis bacteriocin, EntV, produced from the entV (ef1097) locus, as both necessary and sufficient for the reduction of C. albicans 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 C. albicans. 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 C. albicans 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.

http://www.pnas.org/content/114/17/4507.short