Abstrakt

Although the contemporary medicine keeps moving forward, disseminated infections caused by fungal pathogens are an emerging challenge. The dramatic rise of fungal diseases, especially the most life-threatening systemic mycoses is associated with a permanently growing number of immunodeficient patients. Undoubted difficulties in the treatment of fungal infections are caused by lack of highly effective and selective antifungal drugs, as well as the growing number of multi-drug resistance (MDR) fungal strains.Polyene antibiotics, including Nystatin A1, are still one of the most popular drugs for the treatment of fungal infections in humans. Apart from its most desirable features, comprising a high antifungal activity, fungicidal action and ability to overcome the fungal multidrug resistance, the poor water solubility and high mammalian toxicity of Nystatin A1 essentially limits its practical application. One of the solutions to circumvent these disadvantages is a chemical modification of the native drug. This approach, although allows to avoid the toxic effects of additives used for the drug formulations, nevertheless can affect the drug's ability to overcome the fungal multidrug resistance. It is well evidenced that even small changes in the structure of active compounds can eliminate their affinity to the protein targets like, e.g. enzymes, hormones receptors, as well as membrane transporters.Our research program was aimed at the investigation of the effect of modification of polyene macrolides on their ability to overcome the fungal multidrug resistance. In the presented study, we examined the effect of Nystatin A1 (NysA1) modification at the amino group. The subject derivative was N-fructosyl Nystatin A1 (FruNysA1), obtained by the Amadori reaction of the native antibiotic with glucose. The compound forms well water soluble salt with N-methyl glucamine.The antifungal activity of the obtained derivative towards Candida albicans sensitive strain and its multidrug resistant mutants overexpressing protein transporters of the ABC and MFS superfamilies were determined. Studies on membrane permeabilization upon the action of NysA1 and FruNysA1 on drug-sensitive and MDR strains were performed using a propidium iodide (PI) as a fluorescent probe. The affinity of Nystatin A1 and its N-fructosyl derivative to Saccharomyces cerevisiae recombinants strains was analysed by a fluorescence energy transfer method with a plasma membrane probe - DPH.

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