Kamiński Daniel M, Czernel Grzegorz, Murphy Bridget, Runge Benjamin, Magnussen Olaf M, Gagoś Mariusz
Department of Chemistry, University of Life Sciences in Lublin, Akademicka 15, 20-950 Lublin, Poland.
Department of Biophysics, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland.
Biochim Biophys Acta. 2014 Nov;1838(11):2947-53. doi: 10.1016/j.bbamem.2014.08.004. Epub 2014 Aug 12.
Amphotericin B is a Streptomyces nodosus metabolite and one of the oldest polyene antibiotics used in the treatment of invasive systemic fungal infections. Despite its over 50-year existence in clinical practice and the recognition of amphotericin B as the gold standard in the treatment of serious systemic mycosis, it still remains one of the most toxic pharmaceuticals. Understanding of the processes at the molecular levels and the interactions between amphotericin B with lipid membranes containing sterols should elucidate the mechanisms of the action and toxicity of this widely used antibiotic. In this work, we use X-ray reflectivity to study the structural changes on a molecular scale after amphotericin B incorporation. These changes are accompanied by an increase in monolayer surface pressure which is more pronounced for ergosterol - rather than cholesterol-rich membranes. The data indicate that this difference is not due to the higher affinity of amphotericin B towards ergosterol-containing membranes but is rather due to a ~3Angstrom corrugation of the monolayer. Furthermore, the total quantity of amphotericin B incorporated into lipid monolayers containing cholesterol and ergosterol is the same.
两性霉素B是结节链霉菌的代谢产物，是用于治疗侵袭性系统性真菌感染的最古老的多烯抗生素之一。尽管两性霉素B在临床实践中已应用了50多年，并且被公认为是治疗严重系统性真菌病的金标准，但它仍然是毒性最大的药物之一。了解分子水平的过程以及两性霉素B与含甾醇脂质膜之间的相互作用，应该能够阐明这种广泛使用的抗生素的作用和毒性机制。在这项工作中，我们使用X射线反射率来研究两性霉素B掺入后分子尺度上的结构变化。这些变化伴随着单层表面压力的增加，这在富含麦角甾醇而非胆固醇的膜中更为明显。数据表明，这种差异不是由于两性霉素B对含麦角甾醇膜的亲和力更高，而是由于单层约3埃的波纹。此外，掺入含胆固醇和麦角甾醇脂质单层中的两性霉素B总量是相同的。
