Regulation of daptomycin biosynthesis in Streptomyces roseosporus: new insights from genomic analysis and synthetic biology to accelerate lipopeptide discovery and commercial production

-nitrosoguanidine (MNNG) mutagenesis, are available for comparitive studies. DNA sequence analysis of the daptomycin biosynthetic gene clusters (BGCs) from these strains indicates that the high producer has two mutations in a large promoter region that drives the transcription of a giant multicistronic mRNA that includes all nine genes involved in daptomycin biosynthesis. The locations of translational start and stop codons strongly suggest that all nine genes are translationally coupled by overlapping stop and start codons or by 70S ribosome scanning. This report also reviews recent studies on this promoter region that have identified at least ten positive or negative regulatory genes suitable to manipulate by metabolic engineering, synthetic biology and focused mutagenesis for strain improvement. Improvements in daptomycin production will also enable high-level production of novel lipopeptide antibiotics identified by genome mining and combinatorial biosynthesis, and accelerate clinical and commercial development of superior lipopeptide antibiotics.