Abstract
Daptomycin is a clinically important antibiotic approved for the treatment of complicated skin and skin structure infections caused by Gram-positive pathogens, and for the treatment of bacteremia and endocarditis caused by Staphylococcus aureus. Daptomycin and related acidic cyclic lipopeptide antibiotics have ten amino acids in the ring, and exocyclic tails containing one or three amino acids. The N-termini of the exocyclic amino acids are generally coupled to long chain fatty acids. Biosynthesis is initiated by the coupling of fatty acids to the N-terminal amino acids, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms, then cyclization and release of the lipopeptides. The biosynthetic genes for daptomycin, calcium dependent antibiotic (CDA), A54145 and friulimicin have been cloned, sequenced, analyzed bioinformatically, and in some cases genetically or biochemically. The information on the organization and expression of the NRPS and other genes has been exploited to generate combinatorial libraries of hybrid lipopeptide antibiotics related to daptomycin, including several compounds with very good antibacterial activities.
Keywords: nonribosomal peptide synthetase, Streptomyes lividans, acyl carrier protein, dptG gene, A54145, amphomycins, friulimicins
Current Topics in Medicinal Chemistry
Title: Biosynthesis and Genetic Engineering of Lipopeptide Antibiotics Related to Daptomycin
Volume: 8 Issue: 8
Author(s): Richard H. Baltz
Affiliation:
Keywords: nonribosomal peptide synthetase, Streptomyes lividans, acyl carrier protein, dptG gene, A54145, amphomycins, friulimicins
Abstract: Daptomycin is a clinically important antibiotic approved for the treatment of complicated skin and skin structure infections caused by Gram-positive pathogens, and for the treatment of bacteremia and endocarditis caused by Staphylococcus aureus. Daptomycin and related acidic cyclic lipopeptide antibiotics have ten amino acids in the ring, and exocyclic tails containing one or three amino acids. The N-termini of the exocyclic amino acids are generally coupled to long chain fatty acids. Biosynthesis is initiated by the coupling of fatty acids to the N-terminal amino acids, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms, then cyclization and release of the lipopeptides. The biosynthetic genes for daptomycin, calcium dependent antibiotic (CDA), A54145 and friulimicin have been cloned, sequenced, analyzed bioinformatically, and in some cases genetically or biochemically. The information on the organization and expression of the NRPS and other genes has been exploited to generate combinatorial libraries of hybrid lipopeptide antibiotics related to daptomycin, including several compounds with very good antibacterial activities.
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Cite this article as:
Baltz H. Richard, Biosynthesis and Genetic Engineering of Lipopeptide Antibiotics Related to Daptomycin, Current Topics in Medicinal Chemistry 2008; 8 (8) . https://dx.doi.org/10.2174/156802608784221497
DOI https://dx.doi.org/10.2174/156802608784221497 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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