Glycopeptide antibiotic discovery in the genomic era

Glycopeptide antibiotics are essential drugs used to treat infections caused by multi-drug resistant Gram-positive pathogens. There is a continuous need for new antibiotics, including GPAs, to address emerging resistance and offer desirable pharmacological profiles for improved efficacy. Microbial natural products are proven sources of antibiotics, and this source has dominated drug discovery over the past century. Bacteria from the phylum Actinobacteria are particularly renowned for producing a diverse range of bioactive natural products including glycopeptide antibiotics. The traditional approach to mining this resource is through the culture and extraction of natural products followed by assay for cell-killing activity. Unfortunately, this method no longer efficiently yields new antibiotic leads, delivering instead known compounds. Whole-genome sequencing programs on the other hand are revealing thousands of unexplored natural product biosynthetic gene clusters in the chromosomes of Actinobacteria. These gene clusters encode the necessary enzymes, transport and resistance mechanisms, along with regulatory elements for the biosynthesis of a variety of antibiotics. Identification of uncharacterized or cryptic biosynthetic gene clusters to unlock the chemical "dark matter" represents a new direction for the discovery of new drug candidates. This chapter discusses the identification of glycopeptide antibiotic biosynthetic gene clusters in microbial genomes, the improved production of these antibiotics using the GPAHex synthetic biology platform, and methods for their purification.