Biosynthesis of glycopeptides: Prospects for improved antibacterials

Glycopeptide antibiotics are complex natural products biosynthesized by several actinomycete genera. They inhibit bacterial growth by interfering with cell wall biosynthesis. Glycopeptide antibiotics consist of a heptapeptide skeleton highly modified through cross-links of the aromatic moieties. In addition, they are usually further embellished by chlorination, glycosylation, methylation, acylation and/or sulfation. The clinically used glycopeptides vancomycin and teicoplanin have become last resort antibiotics against multi-resistant Gram positive pathogens. In addition, second-generation glycopeptides with improved properties, obtained by semi-synthesis, have been developed. This has created considerable interest in augmenting the structural diversity of glycopeptides by complementing chemical methods, which are limited to few accessible positions, with biological means. The elucidation of the biosynthetic pathways leading to six different compounds in this class has thus expanded the toolbox for structural manipulations. We review the current understanding of glycopeptide biosynthesis, a requisite for producing additional derivatives. In recent years, several novel compounds have been obtained by mutasynthesis, genetic manipulation, chemoenzymatic approaches or a combination thereof. The potential of these methods for creating clinically valuable compounds will be discussed.