Four-Arm δ‑Ornithine-Based Polypeptoids Resensitize Voriconazole against Azole-Resistant C. albicans

Worldwide Candida albicans infections cause a huge burden in healthcare and the efficacy of traditional antifungals is diminished because of the rapid development of antifungal resistance. It is necessary to develop new antifungals or new strategies to make multidrug-resistant (MDR) C. albicans to resensitize to existing antifungal drugs. In this work, a series of 4-arm polypeptoids (FAPs) were synthesized through grafting linear ε-l-lysine or δ-ornithine-based oligopeptides to a trimeric lysine core. The most potent 4R-O7 exhibited excellent activities toward three sensitive and two MDR C. albicans strains with MIC values as low as 24–48 μg/mL (vs 375 μg/mL for ε-polylysine, ε-PL). The mechanism studies revealed that 4R-O7 penetrated the cell membrane and generated ROS to kill cells. 4R-O7 exhibited a synergistic effect (FICI < 0.5) with voriconazole (VOR) and also assisted VOR to restore its efficacy to MDR C. albicans. In addition, the combined use of 4R-O7 and VOR significantly improved the elimination efficacy of mature C. albicans biofilms and enhanced the potency in a mouse subcutaneous C. albicans infection model