Starzyk Joanna, Gruszecki Marcin, Tutaj Krzysztof, Luchowski Rafal, Szlazak Radoslaw, Wasko Piotr, Grudzinski Wojciech, Czub Jacek, Gruszecki Wieslaw I
Department of Biophysics, Institute of Physics, Maria Curie-Skłodowska University , Lublin, Poland.
J Phys Chem B. 2014 Dec 4;118(48):13821-32. doi: 10.1021/jp510245n. Epub 2014 Nov 21.
Amphotericin B (AmB) is a lifesaving antibiotic used to treat deep-seated mycotic infections. Both the pharmaceutical activity and highly toxic side effects of the drug rely on its interaction with biomembranes, which is governed by the molecular organization of AmB. In the present work, we present a detailed analysis of self-assembly of AmB molecules in different environments, interesting from the physiological standpoint, based on molecular spectroscopy techniques: electronic absorption, circular dichroism, steady state and time-resolved fluorescence and molecular dynamic calculations. The results show that, in the water medium, AmB self-associates to dimeric structures, referred to as "parallel" and "antiparallel". AmB dimers can further assemble into tetramers which can play a role of transmembrane ion channels, affecting electrophysiological homeostasis of a living cell. Understanding structural determinants of self-assembly of AmB opens a way to engineering preparations of the drug which retain pharmaceutical effectiveness under reduced toxicity.
两性霉素B（AmB）是一种用于治疗深部真菌感染的救命抗生素。该药物的药理活性和高毒性副作用均依赖于其与生物膜的相互作用，而这种相互作用受AmB的分子组织调控。在本研究中，我们基于分子光谱技术（电子吸收、圆二色性、稳态和时间分辨荧光以及分子动力学计算），对不同环境中AmB分子的自组装进行了详细分析，这些环境从生理学角度来看很有趣。结果表明，在水介质中，AmB自缔合形成二聚体结构，称为“平行”和“反平行”。AmB二聚体可进一步组装成四聚体，后者可发挥跨膜离子通道的作用，影响活细胞的电生理稳态。了解AmB自组装的结构决定因素为设计在降低毒性的情况下仍保留药物有效性的制剂开辟了道路。
