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Genetic Engineering in Streptomyces roseosporus to Produce Hybrid Lipopeptide Antibiotics

2006; Elsevier BV; Volume: 13; Issue: 3 Linguagem: Inglês

10.1016/j.chembiol.2005.12.012

1879-1301

Vivian Miao, Marie-François Coëffet-Le Gal, Kien T. Nguyen, Paul Brian, Julia Penn, Andrew Whiting, Jonathan Steele, DAVID A. KAU, Steve Martin, Robert C. Ford, Trevor Gibson, Mario Bouchard, Stephen K. Wrigley, Richard H. Baltz,

RNA and protein synthesis mechanisms

Daptomycin is a lipopeptide antibiotic produced by a nonribosomal peptide synthetase (NRPS) in Streptomyces roseosporus. The holoenzyme is composed of three subunits, encoded by the dptA, dptBC, and dptD genes, each responsible for incorporating particular amino acids into the peptide. We introduced expression plasmids carrying dptD or NRPS genes encoding subunits from two related lipopeptide biosynthetic pathways into a daptomycin nonproducing strain of S. roseosporus harboring a deletion of dptD. All constructs successfully complemented the deletion in trans, generating three peptide cores related to daptomycin. When these were coupled with incomplete methylation of 1 amino acid and natural variation in the lipid side chain, 18 lipopeptides were generated. Substantial amounts of nine of these compounds were readily obtained by fermentation, and all displayed antibacterial activity against gram-positive pathogens.