Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin
Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin
复制标题
达托霉素与人血清白蛋白位点 II 相互作用的表征
DOI：
10.1016/j.xphs.2020.06.011
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发表时间：
2020
影响因子：
3.8
通讯作者：
Taguchi Kazuaki
中科院分区：
文献类型：
--
作者：
Yamasaki Keishi;Sakurama Keiki;Nishi Koji;Watanabe Hiroshi;Maruyama Toru;Seo Hakaru;Otagiri Masaki;Taguchi Kazuaki
达托霉素是一种环脂肽抗生素，临床上用于治疗革兰氏阳性菌引起的感染，包括耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌。虽然达托霉素显示出高血浆蛋白结合率（90-93%），但我们对结合过程的了解并不广泛。为了更详细地解决这个问题，我们表征了达托霉素与血浆蛋白的结合，结果表明达托霉素与人血清白蛋白（HSA）结合的结合常数远高于另一种血浆蛋白α1-酸性糖蛋白。还发现达托霉素结合到HSA上的单个位点，其被鉴定为位点II。研究结果还表明，然后癸酰基部分的达托霉素渗透到网站II的疏水口袋，这个酰基部分与Tyr 411在网站II的入口处相互作用。由于与位点II的这种选择性相互作用，达托霉素结合被药物（布洛芬或地西泮）和内源性化合物（尿毒症毒素或脂肪酸）显著抑制，这些药物也与位点II强烈结合。在疾病状态下，这种结合抑制可能导致达托霉素的药代动力学和治疗作用发生实质性改变。
Daptomycin, a cyclic lipopeptide antibiotic, is clinically used for the treatment of infections caused by Gram-positive bacteria, including the methicillin-resistantStaphylococcus aureusand the vancomycin-resistantEnterococci. While daptomycin shows high plasma protein binding (90–93%), our knowledge of the binding process is not extensive. To address this issue in more detail, we characterized the binding of daptomycin to plasma proteins and the findings indicate that the association constant for the binding of daptomycin to human serum albumin (HSA) is much higher than that for α1-acid glycoprotein, another plasma protein. Daptomycin was also found to bind to a single site on HSA, which was identified as site II. The findings also suggest that then-decanoyl moiety of daptomycin penetrates into the hydrophobic pocket of site II and that this acyl moiety interacts with Tyr411 at the entrance to site II. Due to this selective interaction with site II, daptomycin binding was significantly inhibited by drugs (ibuprofen or diazepam) and endogenous compounds (uremic toxins or fatty acids) which also strongly bind to site II. In diseased states, such an inhibition in the binding could result in the pharmacokinetics and therapeutic action of daptomycin being substantially altered.