Antifungal Mechanism of Action of Lauryl Betaine Against Skin-Associated Fungus Malassezia restricta

Betaine derivatives are considered major ingredients of shampoos and are commonly used as antistatic and viscosity-increasing agents. Several studies have also suggested that betaine derivatives can be used as antimicrobial agents. However, the antifungal activity and mechanism of action of betaine derivatives have not yet been fully understood. In this study, we investigated the antifungal activity of six betaine derivatives against Malassezia restricta, which is the most frequently isolated fungus from the human skin and is implicated in the development of dandruff. We found that, among the six betaine derivatives, lauryl betaine showed the most potent antifungal activity. The mechanism of action of lauryl betaine was studied mainly using another phylogenetically close model fungal organism, Cryptococcus neoformans, because of a lack of available genetic manipulation and functional genomics tools for M. restricta. Our genome-wide reverse genetic screening method using the C. neoformans gene deletion mutant library showed that the mutants with mutations in genes for cell membrane synthesis and integrity, particularly ergosterol synthesis, are highly sensitive to lauryl betaine. Furthermore, transcriptome changes in both C. neoformans and M. restricta cells grown in the presence of lauryl betaine were analyzed and the results indicated that the compound mainly affected cell membrane synthesis, particularly ergosterol synthesis. Overall, our data demonstrated that lauryl betaine influences ergosterol synthesis in C. neoformans and that the compound exerts a similar mechanism of action on M. restricta.

甜菜碱衍生物被视为洗发产品的核心成分之一，常被用作抗静电剂与增黏剂。多项研究亦表明，甜菜碱衍生物可作为抗菌剂使用。然而，甜菜碱衍生物的抗真菌活性及其作用机制尚未得到完全阐明。本研究针对6种甜菜碱衍生物开展抗真菌活性实验，受试菌株为限制性马拉色菌（Malassezia restricta）——这是人体皮肤最常分离到的真菌，且与头皮屑的发生发展密切相关。实验结果显示，6种甜菜碱衍生物中，月桂基甜菜碱的抗真菌活性最强。鉴于限制性马拉色菌缺乏可用的遗传操作与功能基因组学工具，本研究主要选取系统发育关系较近的模式真菌——新型隐球菌（Cryptococcus neoformans），来探究月桂基甜菜碱的作用机制。本研究利用新型隐球菌基因缺失突变体库开展全基因组反向遗传筛选，结果发现，参与细胞膜合成与完整性维持（尤其是麦角固醇合成）的基因发生突变的菌株，对月桂基甜菜碱呈现高度敏感性。此外，本研究还分析了经月桂基甜菜碱处理后的新型隐球菌与限制性马拉色菌的转录组变化，结果显示该化合物主要影响细胞膜合成过程，尤以麦角固醇合成为甚。综上，本研究数据证实，月桂基甜菜碱可影响新型隐球菌的麦角固醇合成，且该化合物对限制性马拉色菌亦发挥相似的作用机制。