ABSTRACT
Antifungal polyene macrolide antibiotics Amphotericin B (AmB) and Nystatin (NYS) were conjugated through the ω-amino acid linkers with diwalled "molecular umbrellas" composed of spermidine-linked deoxycholic or cholic acids. The presence of "umbrella" substituents modulated biological properties of the antibiotics, especially their selective toxicity. Some of the AmB-umbrella conjugates demonstrated antifungal in vitro activity comparable to that of the mother antibiotic but diminished mammalian toxicity, especially the hemolytic activity. In contrast, antifungal in vitro activity of NYS-umbrella conjugates was strongly reduced and all these conjugates demonstrated poorer than NYS selective toxicity. No correlation between the aggregation state and hemolytic activity of the novel conjugates was found.
Subject(s)
Amphotericin B/analogs & derivatives , Amphotericin B/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Nystatin/analogs & derivatives , Nystatin/pharmacology , Amphotericin B/toxicity , Antifungal Agents/toxicity , Fungi/drug effects , HEK293 Cells , Hemolysis/drug effects , Hep G2 Cells , Humans , Mycoses/drug therapy , Nystatin/toxicity , Polyenes/chemistry , Polyenes/pharmacology , Polyenes/toxicityABSTRACT
6-Sulfo-6-deoxy-D-glucosamine (GlcN6S), 6-sulfo-6-deoxy-D-glucosaminitol (ADGS) and their N-acetyl and methyl ester derivatives have been synthesized and tested as inhibitors of enzymes catalyzing reactions of the UDP-GlcNAc pathway in bacteria and yeasts. GlcN6S and ADGS at micromolar concentrations inhibited glucosamine-6-phosphate (GlcN6P) synthase of microbial origin. The former was also inhibitory towards fungal GlcN6P N-acetyl transferase, but at millimolar concentrations. Both compounds and their N-acetyl derivatives exhibited antimicrobial in vitro activity, with MICs in the 0.125-2.0 mg mL-1 range. Antibacterial but not antifungal activity of GlcN6S was potentiated by D-glucosamine and a synergistic antibacterial effect was observed for combination of ADGP and a dipeptide Nva-FMDP.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Glucosamine/chemical synthesis , Glucosamine/pharmacology , Thiosugars/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/metabolism , Chemistry Techniques, Synthetic , Glucosamine/chemistry , Glucosamine/metabolism , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/antagonists & inhibitors , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/chemistry , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/metabolism , Intracellular Space/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Conformation , Thiosugars/chemical synthesis , Thiosugars/chemistry , Thiosugars/metabolismABSTRACT
Amino sugars are important constituents of a number of biomacromolecules and products of microbial secondary metabolism, including antibiotics. For most of them, the amino group is located at the positions C1, C2 or C3 of the hexose or pentose ring. In biological systems, amino sugars are formed due to the catalytic activity of specific aminotransferases or amidotransferases by introducing an amino functionality derived from L-glutamate or L-glutamine to the keto forms of sugar phosphates or sugar nucleotides. The synthetic introduction of amino functionalities in a regio- and stereoselective manner onto sugar scaffolds represents a substantial challenge. Most of the modern methods of for the preparation of 1-, 2- and 3-amino sugars are those starting from "an active ester" of carbohydrate derivatives, glycals, alcohols, carbonyl compounds and amino acids. A substantial progress in the development of region- and stereoselective methods of amino sugar synthesis has been made in the recent years, due to the application of metal-based catalysts and tethered approaches. A comprehensive review on the current state of knowledge on biosynthesis and chemical synthesis of amino sugars is presented.
