Semisynthetic Amides of Polyene Antibiotic Natamycin.

Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized. Antifungal activities of natamycin derivatives were investigated against , including a panel of clinical isolates and filamentous fungi. Toxicity for mammalian cells was assayed by monitoring antiproliferative activity against human postnatal fibroblasts (HPF) and human embryonic kidney cells (HEK293). By comparing leakage of contents from ergosterol versus cholesterol containing vesicles, a ratio that characterizes the efficacy and safety of natamycin and its derivatives was determined (EI, efficiency index). Ability of all tested semisynthetic natamycines to prevent proliferation of the yeast cells was comparable or even slightly higher to those of parent antibiotic. Interestingly, amide was more potent than natamycin () against all tested strains (MIC values 2 μg/mL vs 8 μg/mL, respectively). Among 7 derivatives, amide with long lipophilic side chains showed the highest and strong antifungal activity in vitro but was more toxic against HPF. In vivo experiments with amide showed in vivo efficacy on a mouse candidemia model with a larger LD/ED ratio in comparison to amphotericin B.