Sweet antibiotics - the role of glycosidic residues in antibiotic and antitumor activity and their randomization

• Published in: FEMS microbiology reviews 2008-08, Vol.32 (5), p.858-889
• Main Authors: KREN, Vladimir, REZANKA, Tomas
• Format: Article
• Language: English
• Subjects: Aglycones; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibiotics; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; antitumor; Antitumor activity; Antitumor agents; Biological activity; Biological and medical sciences; DNA interactions; Fundamental and applied biological sciences. Psychology; Glycopeptides - chemistry; Glycopeptides - pharmacology; glycorandomization; Glycosides; Glycosides - chemistry; Glycosides - pharmacology; Glycosides - physiology; Glycosylation; Microbiology; Mutants; Organic chemistry; Pharmacokinetics; Residues; Selectivity; Structure-Activity Relationship; structure-activity relationships; Vancomycin
• ISSN: 0168-6445; 1574-6976; 1574-6976
• DOI: 10.1111/j.1574-6976.2008.00124.x

A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings - a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure-activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.