Jolanta Grzybowska

Quantitative structure-activity relationships in amphotericin B derivatives

The quantitative structure-activity relationships studies of amphotericin B and its 16 semisynthetic derivatives obtained by modification at carboxyl and amino groups have been done. The results of five biological tests were subjected to principal component analysis, a numerical method useful in the investigation of large sets of data. For some compounds, also, interaction with lipidic vesicles was investigated by spectroscopic methods. The results obtained indicate that: (i) The presence of positively charged nitrogen atom (protonable or bearing fixed charge) is indispensable for biological activity and antibiotic-sterol interaction; (ii) The lack of free carboxyl group in the molecule favours the differentiation between cholesterol and ergosterol containing cells.

Influence of net charge on the aggregation and solubility behaviour of amphotericin B and its derivatives in aqueous media

The poor solubility of polyene antibiotics in aqueous media limits their application in the therapy of systemic fungal infections. In the present paper we have demonstrated that the ionic state (net electrical charge) of the antibiotic molecule is an important factor in determining the aggregation and solubility properties of amphotericin B and its derivatives. A multi-step model of polyene self-association in aqueous media has been proposed as an explanation for the fact that some major differences are observed when aggregation is monitored by different techniques.

MFAME, N-methyl-N-d-fructosyl amphotericin B methyl ester, a new amphotericin B derivative of low toxicity: relationship between self-association and effects on red blood cells

In aqueous solutions N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME), a novel amphotericin B derivative with low animal toxicity, similar to its parent antibiotic, exists in three forms: monomeric, soluble and insoluble aggregates in equilibrium [1]. The aim of our work was to examine the influence of medium composition on the MFAME self-association and the relationship between MFAME self-association and its toxicity towards red blood cells. The toxicity of MFAME in aggregated state towards red blood cells was tested by measuring the induction of potassium leakage and extent of haemolysis. The proportions of antibiotic species present in various aqueous media were determined by analysis of the UV-Vis spectra as a function of the antibiotic concentration. Numeric decomposition of the spectra allowed identification of four spectral species present in MFAME solutions: monomeric and three aggregated forms. Our results indicate that these aggregates, named type I, type II and type III, are different in terms of spectral properties, as well as effectiveness towards red blood cells. Soluble aggregate types I and III are the active forms of MFAME towards erythrocytes. The medium composition seems to be the main factor determining which type of antibiotic aggregate prevails in solution.