Synergistic Effect of β-Amino Acid Polymers and Itraconazole on Reversing Drug Resistance in Candida albicans
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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DAP:Bu系列β-氨基酸聚合物。抗菌测试表明，制备的DAP:Bu共聚物可通过协同增效，有效逆转白色念珠菌(Candida albicans, C. albicans)对伊曲康唑的耐药性，使伊曲康唑的抗真菌最低抑制浓度从单药的>200 μg/mL降低至协同后的3.1 μg/mL，即从无效逆转为高效抗真菌活性。此外，DAP:Bu共聚物在400 μg/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:Bu共聚物能实现高效的协同增效和逆转真菌对伊曲康唑的耐药性，在真菌感染治疗中具有广阔的应用潜力。Abstract: In this study, we design and synthesize a series of β-amino acid polymers that have synergistic antifungal activity with itraconazole. The random copolymers DAP:Bu were obtained by ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides (β-NTA) under room temperature using 4-tert-Butylbenzylamine (tBuBz-NH2) as an initiator, with DL-β-norleucine N-thiocarboxyanhydrides (β-Bu NTA) as hydrophobic monomer and N(α)-Z-DL-2,3-diaminopropionic acid N-thiocarboxyanhydrides (β-DAP NTA) as cationic monomer. The effect of DAP:Bu combined with itraconazole on C. albicans was evaluated by checkerboard antifungal test. The test showed that DAP:Bu 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 >200 μg/mL to 3.1 μg/mL after exposure to DAP:Bu, indicating that the antifungal activity of itraconazole reversed from ineffective to highly effective. In addition, most of DAP:Bu copolymers did not cause significant hemolysis of human red blood cells and fibroblasts toxicity at a high concentration of 400 μg/mL. Our studies demonstrate that the DAP:Bu copolymers can achieve efficient synergistic effect with itraconazole and reverse itraconazole resistance in C. albicans, showing broad potential in the treatment of fungal infections.
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Key words:
- β-amino acid polymers /
- itraconazole /
- synergistic effect /
- reversing fungal resistance /
- antifungal
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图 1 DAP:Bu系列β氨基酸聚合物的合成
Figure 1. Synthetic route of DAP:Bu series of β-amino acid polymers
图 2 C. albicans K1在不同浓度药物联合作用下的具体生长情况
Figure 2. Growth of C. albicans K1 incubated with different concentrations of polymers and itraconazole
表 1 系列聚合物与伊曲康唑的最低抑菌浓度及相互作用模式
Table 1. Interaction modes of polymers and itraconazole and their MIC and FICI values
Polymer MIC alone (μg/mL) MIC combined (μg/mL) FICI Effect itraconazole polymer itraconazole polymer (DAP0.9Bu0.1)20 >200 3.1 6.3 0.8 0.29 Synergistic (DAP0.8Bu0.2)20 >200 3.1 6.3 0.8 0.29 Synergistic (DAP0.7Bu0.3)20 >200 6.3 3.1 1.6 0.27 Synergistic (DAP0.6Bu0.4)20 >200 6.3 4.7 1.6 0.28 Synergistic (DAP0.5Bu0.5)20 >200 12.5 3.1 3.1 0.26 Synergistic 
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