In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis
In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis
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DOI：
10.1128/aac.01890-15
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发表时间：
2015-12-01
影响因子：
4.9
通讯作者：
Lopez-Ribot, Jose L.
中科院分区：
文献类型：
--
作者：
Machado Vila, Taissa Vieira;Chaturvedi, Ashok K.;Lopez-Ribot, Jose L.
产生新的抗白色念珠菌生物膜已成为一个主要的优先事项，因为这种机会致病性真菌形成的生物膜通常与对唑类抗真菌药物的耐药性增加和治疗失败有关。米替膦是一种具有抗真菌活性的烷基磷脂。在这里，我们报道，当在浮游条件下进行测试时，米替福辛对多种氟康唑敏感和耐药的白色念珠菌临床分离株显示出强大的体外活性，包括过度表达外排泵和/或具有明显特征的Erg11突变的分离株。此外，米替氟辛抑制白色念珠菌生物膜的形成，并显示对预形成的生物膜的活性。连续传代实验证实，米特福辛对白念珠菌产生抗性的可能性降低，白念珠菌转录因子突变文库的筛选为米特福辛对浮游和生物膜条件下生长的白念珠菌的活性提供了额外的见解。最后，我们证明了米替福辛局部治疗口咽念珠菌病小鼠模型的体内疗效。总的来说，我们的研究结果证实了米特福辛作为一种有前途的抗真菌候选药物的潜力，特别是在治疗耐唑和生物膜相关的浅表念珠菌病方面。
The generation of a new antifungal against Candida albicans biofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potent in vitro activity against multiple fluconazole-susceptible and -resistant C. albicans clinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibits C. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library of C. albicans transcription factor mutants provided additional insight into the activity of miltefosine against C. albicans growing under planktonic and biofilm conditions. Finally, we demonstrate the in vivo efficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis.