Lipid components of bile increase the protective effect of conjugated bile salts against antifungal drugs
Lipid components of bile increase the protective effect of conjugated bile salts against antifungal drugs
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DOI：
10.1016/j.funbio.2017.08.002
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发表时间：
2017-11-01
期刊：
影响因子：
2.5
通讯作者：
Brock, Matthias
中科院分区：
文献类型：
--
作者：
Hsieh, Shih-Hung;Brock, Matthias
真菌和细菌会持续存在于人类的胆汁中。以前的研究表明，胆汁可以保护这个隐秘的宿主生态位中的白色念珠菌免受抗真菌药物的伤害，为停止抗真菌治疗后肠道的重新定植提供了储备库。胆汁和结合胆盐将抗真菌药物捕获在胶束中，从而降低了它们的生物利用度，并可能促进抗药性的发展。在这里，我们表明胆汁和结合胆盐的保护作用不仅限于白色念珠菌，还可以观察到其他真菌。有趣的是，胆汁而不是结合胆盐导致了白色念珠菌对氟康唑的耐药性，而只有胆汁介导了土曲霉对伏立康唑的耐药性。为了研究胆汁的这种更高的效力，我们的目标是从结合胆盐逐步重建胆汁。不添加磷脂，也不添加不受氮唑保护的饱和脂肪酸。相比之下，补充多不饱和脂肪酸增加了对唑类的抵抗力，并将结合胆盐的临界胶束浓度降低到胆汁的水平。因此，多不饱和脂肪酸对于混合胶束的形成至关重要，因为它具有很高的捕获抗真菌药物的潜力。由于胆道感染很难治疗，因此应该使用重组合成胆汁来测试胆道系统的药物疗效。(C)2017年英国真菌学会。爱思唯尔有限公司出版。保留所有权利。
Fungi and bacteria can persist in the human gall bladder. Previous studies have shown that bile protects Candida albicans in this cryptic host niche from antifungals, providing a reservoir for intestinal re-colonization after discontinuation of antifungal therapy. Bile and conjugated bile salts trap antifungals in micelles, thereby reducing their bioavailability and possibly promoting the development of drug resistance. Here we show that the protective effect of bile and conjugated bile salts is not limited to C. albicans, but also observed with other fungi. Interestingly, bile, but not conjugated bile salts conferred resistance of C. albicans against fluconazole and only bile mediated resistance of Aspergillus terreus against voriconazole. To investigate this higher potency of bile we aimed in a step-wise reconstitution of bile from conjugated bile salts. Neither addition of phospholipids nor saturated fatty acids protected from azoles. In contrast, supplementation with polyunsaturated fatty acids increased azole resistance and decreased the critical micelle concentration of conjugated bile salts to the level of bile. Therefore, polyunsaturated fatty acids are vital for mixed micelle formation with high potential to trap antifungals. As biliary infections are difficult to treat, drug efficacy in the biliary system should be tested by using reconstituted synthetic bile. (C) 2017 British Mycological Society. Published by Elsevier Ltd. All rights reserved.