Significance
There is a critical lack of therapeutic agents to treat infections caused by nongrowing persister forms of methicillin-resistant
Staphylococcus aureus
(MRSA). Although membrane-disrupting agents can kill persister cells, their therapeutic potential has been mostly overlooked because of low selectivity for bacterial versus mammalian membranes. We report that the clinically approved anthelmintic drug bithionol kills MRSA persisters by disrupting membrane lipid bilayers at concentrations that exhibit low levels of toxicity to mammalian cells. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Our results significantly enhance our understanding of bacterial membrane disruption and membrane selectivity.
意义
治疗由产生非生长持久菌体形式的甲氧西林耐药金黄色葡萄球菌(MRSA)引起的感染缺乏有效的治疗方法。虽然破坏细胞膜的药物可以杀死持久菌体,但由于对细菌和哺乳动物膜的选择性较低,其治疗潜力一直被忽视。我们报告了临床上批准的驱虫药物双硫仑可以以对哺乳动物细胞毒性较低的浓度破坏膜脂双层来杀死MRSA持久菌体。双硫仑的选择性是由于哺乳动物膜中含有胆固醇,而细菌膜中没有。我们还表明,膜活性抗微生物药物的抗持久菌体效力与它们增加膜流动性的能力有关。我们的结果显著增强了我们对细菌膜破坏和膜选择性的理解。