β-氨基酸聚合物用于协同增效逆转白色念珠菌对伊曲康唑的耐药性  

Synergistic Effect of β-Amino Acid Polymers and Itraconazole on Reversing Drug Resistance in C.albicans

作　　者：马凯茜 张东辉 施超 顾佳蔚 刘润辉[1] MA Kaiqian;ZHANG Donghui;SHI Chao;GU Jiawei;LIU Runhui(State Key Laboratory of Bioreactor Engineering,Key Laboratory for Ultrafine Materials of Ministry of Education,Research Center for Biomedical Materials of Ministry of Education,School of Materials Science and Engineering,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]华东理工大学生物反应器工程国家重点实验室,超细材料制备与应用教育部重点实验室,教育部医用生物材料工程研究中心,材料科学与工程学院,上海200237

出　　处：《功能高分子学报》2022年第6期532-539,共8页Journal of Functional Polymers

基　　金：国家自然科学基金(22075078,21861162010);上海市优秀学术带头人(20XD1421400)。

摘　　要：设计合成了与伊曲康唑具有协同活性的系列β-氨基酸聚合物。通过β-氨基酸N-硫代羧基酸酐(β-NTA)开环聚合的方法,将不同比例疏水性单体DL-β-正亮氨酸N-羧基硫代羰基环内酸酐(简称Bu)和阳离子单体N(α)-Z-DL-2,3-二氨基丙酸N-羧基硫代羰基环内酸酐(简称DAP)进行共聚,得到了系列β-氨基酸聚合物(DAP_(x)Bu_(y))_(n)。抗菌测试表明,制备的(DAP_(x)Bu_(y))_(n)聚合物可通过协同增效,有效逆转白色念珠菌(C.albicans)对伊曲康唑的耐药性,使伊曲康唑的抗真菌最低抑制质量浓度从单药的大于200μg/mL降低至协同后的3.1μg/mL,即从无效逆转为高效抗真菌活性。此外,(DAP_(x)Bu_(y))_(n)聚合物在400μg/mL的高浓度下基本没有造成明显的人血红细胞溶血和细胞毒性。(DAP_(x)Bu_(y))_(n)聚合物能实现高效协同增效和逆转真菌对伊曲康唑的耐药性。In this study,a series of β-amino acid polymers which have synergistic antifungal activity with itraconazole were designed and synthesized.The random copolymers (DAP_(x)Bu_(y))_(n) were obtained by ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides(β-NTA)under room temperature using 4-tert-Butylbenzylamine(tBuBz-NH_(2))as an initiator,with DL-β-norleucine N-thiocarboxyanhydrides as hydrophobic monomer and N(α)-Z-DL-2,3-diaminopropionic acid Nthiocarboxyanhydrides as cationic monomer.The effect of (DAP_(x)Bu_(y))_(n) combined with itraconazole on C.albicans was evaluated by checkerboard antifungal test.The test showed that (DAP_(x)Bu_(y))_(n) copolymers could effectively reverse itraconazole resistance in C.albicans through synergistic effect,while the minimum inhibitory concentration(MIC)of antifungal of itraconazole was reduced from more than 200μg/mL to 3.1μg/mL after exposure to(DAP_(x)Bu_(y))_(n),indicating that the antifungal activity of itraconazole reversed from ineffective to highly effective.In addition,most of (DAP_(x)Bu_(y))_(n) copolymers did not cause significant hemolysis of human red blood cells and fibroblasts toxicity at a high concentration of 400μg/mL.Our studies demonstrate that the(DAP_(x)Bu_(y))_(n) copolymers can achieve efficient synergistic effect with itraconazole and reverse itraconazole resistance in C.albicans,showing broad potential in the treatment of fungal infections.

关 键 词：β-氨基酸聚合物 伊曲康唑 协同增效 逆转真菌耐药性 抗真菌 

分 类 号：R318.08[医药卫生—生物医学工程]