Nystatin, a polyene macrolide antibiotic produced by Streptomyces noursei is used as an antifungal drug for the treatment of broad spectrum of superficial, oral and gastrointestinal fungal diseases. Its possible application in chemotherapy of disseminated fungal infections is precluded, due to the high mammalian toxicity, including a hemolytic effect.

Research efforts at our laboratory are aimed at the improvement of the chemotherapeutic index of polyene macrolide antibiotics by their rational chemical modification. We previously showed that mammalian toxicity of amphotericin B could be strongly reduced due to the chemical modification of the amino group of mycosamine.^1,2 The same rationale was now applied for the construction of N-alkyl derivatives of nystatin. Novel compounds were synthesized upon Michaelis addition of N-substituted maleimides to nystatin under mild conditions The new nystatin derivatives were tested for antifungal in vitro activity, hemolytic activity and induction of potassium leakage from fungal and mammalian cells. Some of the novel compounds demonstrated substantial reduction of mammalian toxicity in comparison with nystatin, while their antifungal efficacy was only slightly diminished. Multidrug-resistant clinical Candida albicans strains demonstrated similar susceptibility to novel N-alkyl derivatives of nystatin as their drug-sensitive counterparts.

1. Grzybowska, J., Sowiński, P., Gumieniak, J., Zieniawa, T., Borowski, E., J. Antibiot., 50, 709-711 (1997); 2.   Ślisz, M., Cybulska, B., Grzybowska, J., Czub, J., Prasad, R., Borowski, E., J. Antibiot., 60, 436-446 (2007)

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