Institute of Pharmaceutical Science, King's College London, London, UK.
Sci Rep. 2012;2:778. doi: 10.1038/srep00778. Epub 2012 Oct 29.
Over the last 50 years or so, amphotericin has been widely employed in treating life-threatening systemic fungal infections. Its usefulness in the clinic, however, has always been circumscribed by its dose-limiting side-effects, and it is also now compromised by an increasing incidence of pathogen resistance. Combating these problems through development of new anti-fungal agents requires detailed knowledge of the drug's molecular mechanism, but unfortunately this is far from clear. Neutron diffraction studies of the drug's incorporation within lipid-sterol membranes have here been performed to shed light on this problem. The drug is shown to disturb the structures of both fungal and mammalian membranes, and co-localises with the membrane sterols in a manner consistent with trans-membrane pore formation. The differences seen in the membrane lipid ordering and in the distributions of the drug-ergosterol and drug-cholesterol complexes within the membranes are consistent with the drug's selectivity for fungal vs. human cells.
在过去的 50 年左右的时间里，两性霉素已被广泛用于治疗危及生命的系统性真菌感染。然而，其在临床上的应用一直受到其剂量限制的副作用的限制，而且现在也受到病原体耐药性不断增加的影响。通过开发新的抗真菌药物来对抗这些问题，需要详细了解药物的分子机制，但不幸的是，这一点远未明确。本文通过对药物在脂质-甾醇膜中的掺入进行中子衍射研究，来阐明这一问题。研究表明，该药物会干扰真菌和哺乳动物膜的结构，并以与跨膜孔形成一致的方式与膜甾醇共定位。在膜脂质有序性以及药物-麦角固醇和药物-胆固醇复合物在膜内的分布方面观察到的差异，与药物对真菌与人类细胞的选择性一致。
