Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane.
Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane.
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DOI：
10.1016/j.bmc.2015.07.009
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发表时间：
2015-09
影响因子：
3.5
通讯作者：
Tomoya Yamamoto;Yuichi Umegawa;H. Tsuchikawa;N. Matsumori;S. Hanashima;M. Murata;R. Haser;B. Rawlings;P. Caffrey
中科院分区：
文献类型：
--
作者：
Tomoya Yamamoto;Yuichi Umegawa;H. Tsuchikawa;N. Matsumori;S. Hanashima;M. Murata;R. Haser;B. Rawlings;P. Caffrey
两性霉素B（AmB）是一种多烯大环内酯类抗生素，广泛用于治疗支原体感染。在本文中，我们专注于使用7-oxo-AmB，7α-OH-AmB和7β-OH-AmB的AmB的多元醇部分在甾醇选择性中的作用。从7-氧代-AmB制备7-OH类似物。它们在脂质体中的K+通量活性表明，在多元醇部分上引入额外的酮或羟基降低了原始活性。这些衍生物的构象分析表明，分子内的氢键网络可能会影响大环内酯环的构象刚性，并稳定膜中的活性构象。此外，柔性多元醇导致整个大环内酯环构象的不稳定，导致甾醇选择性的损失。
Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K+flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity.