Glycopeptides: An old but up-to-date successful antibiotic class

Abstract

Glycopeptides are one of the oldest but still critically important antibiotic class that target Gram-positive pathogens. They are used as essential drugs for the treatment of life-threatening infections of relevant pathogens such as Staphylococcus aureus, Enterococcus spp., and Clostridium difficile. Antibacterial glycopeptides arrest bacterial cell wall biosynthesis by binding to the acyl-d-alanyl-d-alanine terminus of the nascent peptidoglycan, blocking its extracellular polymerization, and subsequently inhibiting cell growth and division. Chemically, these agents consist of a heptapeptide core structure that is transformed in the mature active antibiotic by intramolecular cyclizations among aromatic amino acid residues and by addition of glycosidic moieties, chlorine atoms, and occasionally lipid chains. First-generation glycopeptides (vancomycin and teicoplanin) are natural products from soil actinomycetes. Second-generation molecules (dalbavancin, oritavancin, telavancin) are produced by chemical modification of natural products. Glycopeptide resistance required nearly 30 years to appear following clinical introduction of vancomycin. High-level resistance is due to a collection of genes (named van) that reorder cell wall biosynthesis enabling bacteria to bypass the critical steps susceptible to inhibition by vancomycin and other glycopeptide antibiotics. There have been various efforts, with mixed success, to identify novel glycopeptide structures able to circumvent high-level glycopeptide resistance. This chapter is an overview on the features, mode of action, mechanism of resistance, biosynthesis of this old but up-to-date successful antibiotic class.