Abstract:
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-NH
2) 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.