Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics.

Julia Borzyszkowska-Bukowska,Jakub Jurasz,Paweł Szczeblewski,Iwona Gabriel,Katarzyna Kozłowska-Tylingo,Sławomir Milewski,Piotr Szweda,Justyna Górska,Tomasz Laskowski

doi:10.3390/ijms221810108

Julia Borzyszkowska-Bukowska, Jakub Jurasz + Show 7 more

Open Access

https://doi.org/10.3390/ijms221810108

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Abstract

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans → all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

Highlights

We show that the all-trans isomers of Candicidin D, Partricin A and Partricin B, demonstrate an improved selective toxicity
Candicidin D (CndD) is the main component of Candicidin complex produced by Streptomyces griseus
The previously noted remarkably higher antifungal in vitro activity of original aromatic heptaene macrolides (AHMs) in BDS medium in comparison with that of Amphotericin B [15] was confirmed in our hands but not observed in RPMI 1640 medium under conditions recommended by CLSI [17]

Summary

Introduction

Polyene macrolide antibiotics produced by Streptomyces spp. demonstrate antifungal activity. They are characterized by a large macrocyclic lactone ring (macronolide) containing a system of 3–7 conjugated double bonds and a number of hydrophilic substituents, including a glycosidically bound aminosugar, most often D-mycosamine (3,6-dideoxy-3amino-D-mannose) [1]. Heptaenes fall into two major categories: non-aromatic heptaenes (including AmB) and aromatic heptaene macrolides (AHMs). The latter contain the p-aminoacetophenone moiety attached to an aliphatic sidechain and exhibit the cis-trans geometry of the heptaene chromophore, in contrast to all-trans configuration in non-aromatic heptaenes [3]

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Discussion

Conclusion