Department of Biochemistry of Membranes, Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11156-9. doi: 10.1073/pnas.1203375109. Epub 2012 Jun 25.
The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.
有限的治疗手段和越来越多的真菌对多种抗真菌药物产生耐药的报道，使得真菌感染成为一个主要的治疗挑战。多烯类抗生素是唯一一组通过与主要真菌甾醇麦角固醇的特异性相互作用直接靶向质膜的抗真菌抗生素，通常导致膜通透性增加。与其他在膜中形成孔的多烯类抗生素不同，那他霉素的作用模式仍然不清楚，但与膜通透性增加无关。在这里，我们证明那他霉素通过立即抑制氨基酸和葡萄糖穿过质膜的运输来抑制酵母和真菌的生长。这归因于麦角固醇特异性和可逆的膜转运蛋白抑制。据推测，质膜蛋白的固醇依赖性抑制是所有多烯类抗生素的一种通用作用模式，其中一些抗生素已被证明还能使质膜通透性增加。我们的结果表明，甾醇-蛋白相互作用对于蛋白质功能至关重要，即使对于那些不被认为存在于富含甾醇的区域的蛋白也是如此。
