chloroeremomycin and balhimycin

Glycopeptide antibiotics are a class of widely known natural compounds produced by Actinomycetes. Vancomycin, the first member of the glycopeptide family to be discovered, was described in 1955 and used as an antibiotic soon thereafter. During the past 50 years numerous contributions on the structure, mode of action, and therapeutic features of vancomycin have been published. Recently, there has been considerable progress in elucidating the biosynthesis of glycopeptide antibiotics by combining molecular biology and analytical chemistry methods. Here, we provide an overview of the current knowledge regarding biosynthetic glycopeptide assembly.

Topics: Actinobacteria; Amino Acids, Aromatic; Anti-Bacterial Agents; Peptide Synthases; Teicoplanin; Vancomycin

The bal, cep, dbv, sta and tcp gene clusters specify the biosynthesis of the glycopeptide antibiotics balhimycin, chloroeremomycin, A40926, A47934 and teicoplanin, respectively. These structurally related compounds share a similar mechanism of action in their inhibition of bacterial cell wall formation. Comparative sequence analysis was performed on the five gene clusters. Extensive conserved synteny was observed between the bal and cep clusters, which direct the synthesis of very similar compounds but originate from two different species of the genus Amycolatopsis. All other cluster pairs show a limited degree of conserved synteny, involving biosynthetically functional gene cassettes: these include those involved in the synthesis of the carbon backbone of two non-proteinogenic amino acids; in the linkage of amino acids 1--3 and 4--7 in the heptapeptide; and in the formation of the aromatic cross-links. Furthermore, these segments of conserved synteny are often preceded by conserved intergenic regions. Phylogenetic analysis of protein families shows several instances in which relatedness in the chemical structure of the glycopeptides is not reflected in the extent of the relationship of the corresponding polypeptides. Coherent branchings are observed for all polypeptides encoded by the syntenous gene cassettes. These results suggest that the acquisition of distinct, functional genetic elements has played a significant role in the evolution of glycopeptide gene clusters, giving them a mosaic structure. In addition, the synthesis of the structurally similar compounds A40926 and teicoplanin appears as the result of convergent evolution.

Topics: Actinomycetales; Anti-Bacterial Agents; Base Sequence; Biological Evolution; Genes, Bacterial; Molecular Sequence Data; Multigene Family; Phylogeny; Ristocetin; Sequence Homology, Nucleic Acid; Teicoplanin; Vancomycin