Guanylation Significantly Enhances the Antifungal Activity of Poly(α-lysine)

AMP-mimicking polymers have the potential to serve as an alternative to small-molecule antifungal drugs. Herein, we synthesized four different molecular weight poly(α-lysine) (α-PLn, n = 1–4) and further modified α-PLn to afford guanylated α-PLn (α-PLn-Gx, where x denotes the percentage of guanylation) with enhanced antifungal activities. α-PLn exhibited good antibacterial activities against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), with minimal inhibitory concentration (MIC) values of 24–96 μg/mL, but it did not show antifungal activities against Candida albicans, Candida parapsilosis, Candida krusei, and Candida glabrata, except for Candida tropicalis (MIC < 3 μg/mL). After guanylation, the antifungal activities of α-PLn-Gx against C. albicans, C. krusei, and C. parapsilosis were significantly improved when x ≥ 80 and the MIC values of α-PL3-G100 were reduced by >32-fold, 64-fold, and >16-fold, respectively, compared to that of the corresponding α-PL3. The mechanistic studies demonstrated that α-PL3-G100 disrupted the integrity of cell membranes of C. albicans.