A Novel Small Molecule Inhibitor of Candida albicans Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance.
A Novel Small Molecule Inhibitor of Candida albicans Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance.
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DOI：
10.1038/npjbiofilms.2015.12
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发表时间：
2015
影响因子：
9.2
通讯作者：
Lopez-Ribot JL
中科院分区：
文献类型：
--
作者：
Pierce CG;Chaturvedi AK;Lazzell AL;Powell AT;Saville SP;McHardy SF;Lopez-Ribot JL
白色念珠菌是人类最常见的真菌感染念珠菌病的主要病原体。念珠菌病是世界范围内第三至第四大最常见的医院感染，因为人类的这种正常感染在不断扩大的免疫和医学受损患者群体中引起机会性感染。这些感染通常与生物膜形成有关，这使治疗复杂化并导致不可接受的高死亡率。为了解决对新抗真菌药物的迫切需求，我们在化学库（NOVACore）中对20，000个小分子进行了高含量筛选，以鉴定抑制C.白色念珠菌生物膜形成，并进行了一系列后续研究，以检查所鉴定的化合物的体外和体内活性。筛选鉴定了一系列新的二氮杂螺-癸烷结构类似物，其主要代表生物活性化合物。对该系列化合物的表征表明，它抑制了与C.白念珠菌毒力，最显著的是生物膜形成和粘附，而对总体生长或引发抗性没有影响。该化合物在侵袭性和口腔念珠菌病的临床相关小鼠模型中表现出体内活性，因此代表了抗真菌药物开发的有希望的领先者。此外，这些结果为实施针对C.白色念珠菌和其他真菌感染，不太可能促进耐药性的出现。
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. 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. The screen identified a novel series of diazaspiro-decane structural analogs that 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 antivirulence approaches against C. albicans and other fungal infections that would be less likely to foster the emergence of resistance.