Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis
Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis
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DOI：
10.1128/aac.02649-13
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发表时间：
2014-07-01
影响因子：
4.9
通讯作者：
Diamond, Gill
中科院分区：
文献类型：
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作者：
Ryan, Lisa K.;Freeman, Katie B.;Diamond, Gill
治疗口腔念珠菌病迫切需要新的广谱活性抗真菌药物，这些药物不仅对许多种类的念珠菌（包括耐药菌株）有活性，而且还能逃避可能导致耐药性的微生物对策。宿主防御肽（Host defense peptide, hdp）可为此类药物的开发提供基础。为此，我们开发了完全合成的小分子非肽hdp模拟物，以提高安全性和其他药物性能。在这里，我们描述了几种HDP模拟物的鉴定，它们对白色念珠菌和其他种类的念珠菌具有广泛的活性，快速杀真菌，对酵母和菌丝培养物具有活性，并且对哺乳动物细胞具有低细胞毒性。重要的是，假丝酵母对共生菌的特异性也很明显，从而最大限度地减少了对内源性微生物群的潜在损害，否则可能有利于真菌的过度生长。三种化合物在两种不同的口腔念珠菌病小鼠模型中作为局部药物进行了测试，发现它们具有很高的活性。单次给药后，受感染动物舌头中的念珠菌总负荷减少至3个原木。这些研究突出了HDP模拟物作为治疗口腔念珠菌病的抗真菌武器的新工具的潜力。
There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.