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The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae

  • Original Paper-JMBM
  • Published:
Journal of Industrial Microbiology and Biotechnology

Abstract

Ca2+-dependent cyclic lipodepsipeptides are an emerging class of antibiotics for the treatment of infections caused by Gram-positive pathogens. These compounds are synthesized by nonribosomal peptide synthetase (NRPS) complexes encoded by large gene clusters. The gene cluster encoding biosynthetic pathway enzymes for the Streptomyces fradiae A54145 NRP was cloned from a cosmid library and characterized. Four NRPS-encoding genes, responsible for subunits of the synthetase, as well as genes for accessory functions such as acylation, methylation and hydroxylation, were identified by sequence analysis in a 127 kb region of DNA that appears to be located subterminally in the bacterial chromosome. Deduced epimerase domain-encoding sequences within the NRPS genes indicated a d-stereochemistry for Glu, Lys and Asn residues, as observed for positionally analogous residues in two related compounds, daptomycin, and the calcium-dependent antibiotic (CDA) produced by Streptomyces roseosporus and Streptomyces coelicolor, respectively. A comparison of the structure and the biosynthetic gene cluster of A54145 with those of the related peptides showed many similarities. This information may contribute to the design of experiments to address both fundamental and applied questions in lipopeptide biosynthesis, engineering and drug development.

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Acknowledgements

The authors would like to thank J. McMenanim and L. Thurston for technical assistance, and S.K. Wrigley for reviewing and discussing the manuscript.

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Authors and Affiliations

  1. Cubist Pharmaceuticals Inc., 65 Hayden Av., Lexington, MA, 02421, USA

    Vivian Miao, Renee Brost, Joanne Chapple, Kevin She, Marie-François Coëffet-Le Gal & Richard H. Baltz

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  1. Vivian Miao
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  2. Renee Brost
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  3. Joanne Chapple
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  4. Kevin She
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  5. Marie-François Coëffet-Le Gal
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  6. Richard H. Baltz
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Corresponding author

Correspondence to Richard H. Baltz.

Additional information

Note: A patent application on the sequence of the A54145 gene cluster was published (PCT Int. Appl., W003060127A2) during the preparation of this manuscript. A small deletion of 67 nucleotides (nucleotides 56952–57018) was observed relative to the sequence assembled in this study. The present sequence, obtained from a library clone, was confirmed by sequencing products from replicate PCR amplifications of the region in question from two stocks of S. fradiae DNA.

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Miao, V., Brost, R., Chapple, J. et al. The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae . J IND MICROBIOL BIOTECHNOL 33, 129–140 (2006). https://doi.org/10.1007/s10295-005-0028-5

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  • DOI: https://doi.org/10.1007/s10295-005-0028-5

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