BACKGROUND/OBJECTIVES Candida albicans is the principal causative agent of candidiasis, the most common fungal infection in humans. Candidiasis represents the third-to-fourth most frequent nosocomial infection worldwide, as this normal commensal of humans causes opportunistic infections in an expanding population of immune- and medically-compromised patients. These infections are frequently associated with biofilm formation, which complicates treatment and contributes to unacceptably high mortality rates. METHODS To address the pressing need for new antifungals we have performed a high content screen of 20,000 small molecules in a chemical library (NOVACore™) to identify compounds that inhibit C. albicans biofilm formation, and conducted a series of follow-up studies to examine the in vitro and in vivo activity of the identified compounds. RESULTS The screen identified a novel series of diazaspiro-decane structural analogs which were largely represented among the bioactive compounds. Characterization of the leading compound from this series indicated that it inhibits processes associated with C. albicans virulence, most notably biofilm formation and filamentation, without having an effect on overall growth or eliciting resistance. This compound demonstrated in vivo activity in clinically-relevant murine models of both invasive and oral candidiasis and as such represents a promising lead for antifungal drug development. Furthermore, these results provide proof of concept for the implementation of anti-virulence approaches against C. albicans and other fungal infections that would be less likely to foster the emergence of resistance.

中文翻译：

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一种新型的白色念珠菌生物膜形成，细丝化和毒力小分子抑制剂，具有低的抗药性。

背景/目的白色念珠菌是念珠菌病的主要病原体，念珠菌病是人类最常见的真菌感染。念珠菌病是全世界医院中最常见的第三至第四名感染，因为这种正常的人类行为会引起越来越多的免疫和医学受损患者的机会感染。这些感染通常与生物膜形成有关，这使治疗变得复杂，并导致无法接受的高死亡率。方法为了满足对新型抗真菌剂的紧迫需求，我们在化学文库（NOVACore™）中对20,000个小分子进行了高含量筛选，以鉴定抑制白色念珠菌生物膜形成的化合物，并进行了一系列后续研究，以检查鉴定化合物的体外和体内活性。结果筛选确定了一系列新的二氮杂螺并癸烷结构类似物，这些类似物在生物活性化合物中占很大比例。该系列中主要化合物的表征表明，它抑制了与白色念珠菌毒力相关的过程，最明显的是生物膜的形成和丝化，而没有影响总体生长或引起抗药性。该化合物在侵袭性和口腔念珠菌病的临床相关鼠类模型中均具有体内活性，因此代表了抗真菌药物开发的有前途。此外，这些结果为针对白色念珠菌和其他真菌感染的抗毒方法的实施提供了概念验证，因为这种方法不太可能促进耐药性的出现。