Antibiotic-sterol interactions provide insight into the selectivity of natural aromatic analogues of amphotericin B and their photoisomers

Abstract

Aromatic heptaene macrolides (AHMs) belong to the group of polyene macrolide antifungal antibiotics. Members of this group were the first to be used in the treatment of systemic fungal infections. Amphotericin B (AmB), a non-aromatic representative of heptaene macrolides, is of significant clinical importance in the treatment of internal mycoses. It includes the all-trans heptaene chromophore, whereas the native AHMs contain two cis-type (Z) double bonds within the chromophore system. Lately we have proven that it is possible to obtain AHMs’ stable derivatives in the form of all-trans (AmB-type) isomers by photochemical isomerization. Our further studies have shown that such alteration leads to the improvement of their selective toxicity in vitro. Computational experiments carried out so far were only an initial contribution in the investigation of the molecular basis of the mechanism of action of AHMs and did not provide explanation to observed differences in biological activity between the native (cis-trans) and isomeric (all-trans) AHMs. Herein, we presented the results of two-dimensional metadynamics studies upon AmB and its aromatic analogues (AHMs), regarding preferable binary antibiotic/sterol complexes orientation, as well as more detailed research on the behaviour of AHMs’ alkyl-aromatic side chain in cholesterol- or ergosterol-enriched lipid bilayers.