Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics

Chemistry & Biology
Vivian MiaoRichard H Baltz

Abstract

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.

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Citations

May 15, 2010·Journal of Industrial Microbiology & Biotechnology·Richard H Baltz
Aug 10, 2011·Journal of Industrial Microbiology & Biotechnology·Richard H Baltz
Jan 26, 2008·Molecular Pharmaceutics·Elizabeth A FelnagleMichael G Thomas
Jul 22, 2010·The Journal of Antibiotics·Richard H Baltz
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