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

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_xBu_y)_n 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 as hydrophobic monomer and N(α)-Z-DL-2,3-diaminopropionic acid N-thiocarboxyanhydrides as cationic monomer. The effect of (DAP_xBu_y)_n combined with itraconazole on C. albicans was evaluated by checkerboard antifungal test. The test showed that (DAP_xBu_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 200 μg/mL to 3.1 μg/mL after exposure to (DAP_xBu_y)_n, indicating that the antifungal activity of itraconazole reversed from ineffective to highly effective. In addition, most of (DAP_xBu_y)_n 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_xBu_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.