1887

Abstract

Daptomycin is a 13 amino acid, cyclic lipopeptide produced by a non-ribosomal peptide synthetase (NRPS) mechanism in . A 128 kb region of DNA was cloned and verified by heterologous expression in to contain the daptomycin biosynthetic gene cluster (). The cloned region was completely sequenced and three genes (, , ) encoding the three subunits of an NRPS were identified. The catalytic domains in the subunits, predicted to couple five, six or two amino acids, respectively, included a novel activation domain and amino-acid-binding pocket for incorporating the unusual amino acid -kynurenine (Kyn), three types of condensation domains and an extra epimerase domain (E-domain) in the second module. Novel genes (, ) whose products likely work in conjunction with a unique condensation domain to acylate the first amino acid, as well as other genes (, ) probably involved in supply of the non-proteinogenic amino acids -3-methylglutamic acid and Kyn, were located next to the NRPS genes. The unexpected E-domain suggested that daptomycin would have -Asn, rather than -Asn, as originally assigned, and this was confirmed by comparing stereospecific synthetic peptides and the natural product both chemically and microbiologically.

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2005-05-01
2024-03-29
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References

  1. Akins R. L., Rybak M. J. 2001; Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 45:454–459 [CrossRef]
    [Google Scholar]
  2. Alborn W. E. Jr, Allen N. E., Preston D. A. 1991; Daptomycin disrupts membrane potential in growing Staphylococcus aureus. Antimicrob Agents Chemother 35:2282–2287 [CrossRef]
    [Google Scholar]
  3. Allen N. E., Alborn W. E., Hobbs J. N. Jr Jr 1991; Inhibition of membrane potential-dependent amino acid transport by daptomycin. Antimicrob Agents Chemother 35:2639–2642 [CrossRef]
    [Google Scholar]
  4. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. 1990; Basic local alignment search tool. J Mol Biol 215:403–410 [CrossRef]
    [Google Scholar]
  5. Atherton E., Sheppard R. C. 1989 Solid Phase Peptide Synthesis: a Practical Approach Oxford: IRL Press;
    [Google Scholar]
  6. Baltz R. H. 1997; Lipopeptide antibiotics produced by Streptomyces roseosporus and Streptomyces fradiae . In Biotechnology of Antibiotics pp 415–435 Edited by Strohl W. R. New York: Marcel Dekker;
    [Google Scholar]
  7. Baltz R. H., McHenney M. A., Hosted T. J. 1997; Genetics of lipopeptide antibiotic biosynthesis in Streptomyces fradiae A54145 and Streptomyces roseosporus A21978C. In Developments in Industrial Microbiology pp 93–98 Edited by Baltz R. H., Hegeman G. D., Skatrud P. L. Fairfax, VA: Society for Industrial Microbiology;
    [Google Scholar]
  8. Barry A. L., Fuchs P. C., Brown S. D. 2001; In vitro activities of daptomycin against 2,789 clinical isolates from 11 North American medical centers. Antimicrob Agents Chemother 45:1919–1922 [CrossRef]
    [Google Scholar]
  9. Bentley S. D., Chater K. F., Cerdeno-Tarraga A. M. 40 other authors 2002; Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147 [CrossRef]
    [Google Scholar]
  10. Bernhardt A., Drewello M., Schutkowski M. 1997; The solid-phase synthesis of side-chain-phosphorylated peptide-4-nitroanilides. J Pept Res 50:143–152
    [Google Scholar]
  11. Boeck L. D., Fukuda D. S., Abbott B. J., Debono M. 1988; Deacylation of A21978C, an acidic lipopeptide antibiotic complex, by Actinoplanes utahensis . J Antibiot 41:1085–1092 [CrossRef]
    [Google Scholar]
  12. Brown D., Hitchcock M. J., Katz E. 1986; Purification and characterization of kynurenine formamidase activities from Streptomyces parvulus. Can J Microbiol 32:465–472 [CrossRef]
    [Google Scholar]
  13. Bruner S. D., Weber T., Kohli R. M., Schwarzer D., Marahiel M. A., Walsh C. T., Stubbs M. T. 2002; Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE. Structure 10:301–310 [CrossRef]
    [Google Scholar]
  14. Butler A. R., Bate N., Cundliffe E. 1999; Impact of thioesterase activity on tylosin biosynthesis in Streptomyces fradiae. Chem Biol 6:287–292 [CrossRef]
    [Google Scholar]
  15. Campelo A. B., Gil J. A. 2002; The candicidin gene cluster from Streptomyces griseus IMRU 3570. Microbiology 148:51–59
    [Google Scholar]
  16. Cha R., Brown W. J., Rybak M. J. 2003; Bactericidal activities of daptomycin, quinupristin-dalfopristin, and linezolid against vancomycin-resistant Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 47:3960–3963 [CrossRef]
    [Google Scholar]
  17. Challis G. L., Ravel J. 2000; Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett 187:111–114 [CrossRef]
    [Google Scholar]
  18. Challis G. L., Ravel J., Townsend C. A. 2000; Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem Biol 7:211–224 [CrossRef]
    [Google Scholar]
  19. Chan W. C., White P. D. 2000 Fmoc Solid Phase Peptide Synthesis: a Practical Approach Oxford: Oxford University Press;
    [Google Scholar]
  20. Clugston S. L., Sieber S. A., Marahiel M. A., Walsh C. T. 2003; Chirality of peptide bond-forming condensation domains in nonribosomal peptide synthetases: the C5 domain of tyrocidine synthetase is a (D)C(L) catalyst. Biochemistry 42:12095–12104 [CrossRef]
    [Google Scholar]
  21. Debono M., Barnhart M., Carrell C. B. & 7 other authors; 1987; A21978C, a complex of new acidic peptide antibiotics: isolation, chemistry, and mass spectral structure elucidation. J Antibiot 40:761–777 [CrossRef]
    [Google Scholar]
  22. Debono M., Abbott B. J., Molloy R. M. & 9 other authors; 1988; Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032. J Antibiot 41:1093–1105 [CrossRef]
    [Google Scholar]
  23. Doekel S., Marahiel M. A. 2000; Dipeptide formation on engineered hybrid peptide synthetases. Chem Biol 7:373–384 [CrossRef]
    [Google Scholar]
  24. Du L., Sanchez C., Chen M., Edwards D. J., Shen B. 2000; The biosynthetic gene cluster for the antitumor drug bleomycin from Streptomyces verticillus ATCC 15003 supporting functional interactions between nonribosomal peptide synthetases and a polyketide synthase. Chem Biol 7:623–642 [CrossRef]
    [Google Scholar]
  25. Fields G. B., Noble R. L. 1990; Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 35:161–214
    [Google Scholar]
  26. Frengen E., Weichenhan D., Zhao B., Osoegawa K., van Geel M., de Jong P. J. 1999; A modular, positive selection bacterial artificial chromosome vector with multiple cloning sites. Genomics 58:250–253 [CrossRef]
    [Google Scholar]
  27. Heathcote M. L., Staunton J., Leadlay P. F. 2001; Role of type II thioesterases: evidence for removal of short acyl chains produced by aberrant decarboxylation of chain extender units. Chem Biol 8:207–220 [CrossRef]
    [Google Scholar]
  28. Heinzelmann E., Berger S., Puk O., Reichenstein B., Wohlleben W., Schwartz D. 2003; A glutamate mutase is involved in the biosynthesis of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis . Antimicrob Agents Chemother 47:447–457 [CrossRef]
    [Google Scholar]
  29. Hitchcock M. J., Katz E. 1988; Purification and characterization of tryptophan dioxygenase from Streptomyces parvulus . Arch Biochem Biophys 261:148–160 [CrossRef]
    [Google Scholar]
  30. Hojati Z., Milne C., Harvey B. 9 other authors 2002; Structure, biosynthetic origin, and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor . Chem Biol 9:1175–1187 [CrossRef]
    [Google Scholar]
  31. Hosted T. J., Baltz R. H. 1996; Mutants of Streptomyces roseosporus that express enhanced recombination within partially homologous genes. Microbiology 142:2803–2813 [CrossRef]
    [Google Scholar]
  32. Hosted T. J., Baltz R. H. 1997; Use of rpsL for dominance selection and gene replacement inStreptomyces roseosporus . J Bacteriol 179:180–186
    [Google Scholar]
  33. Huang J., Lih C. J., Pan K. H., Cohen S. N. 2001; Global analysis of growth phase responsive gene expression and regulation of antibiotic biosynthetic pathways in Streptomyces coelicolor using DNA microarrays. Genes Dev 15:3183–3192 [CrossRef]
    [Google Scholar]
  34. Huber F. M., Pieper R. L., Tietz A. J. 1988; The formation of daptomycin by supplying decanoic acid to Streptomyces roseosporus cultures producing the antibiotic complex A21978C. J Biotechnol 7:283–292 [CrossRef]
    [Google Scholar]
  35. Ikeda H., Ishikawa J., Hanamoto A., Shinose M., Kikuchi H., Shiba T., Sakaki Y., Hattori M, Ōmura S. 2003; Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis . Nat Biotechnol 21:526–531 [CrossRef]
    [Google Scholar]
  36. Kieser T., Bibb M. J., Buttner M. J., Chater K. F., Hopwood D. 2000 Practical Streptomyces Genetics Norwich: John Innes Foundation;
    [Google Scholar]
  37. Kim B. S., Cropp T. A., Beck B. J., Sherman D. H., Reynolds K. A. 2002; Biochemical evidence for an editing role of thioesterase II in the biosynthesis of the polyketide pikromycin. J Biol Chem 277:48028–48034 [CrossRef]
    [Google Scholar]
  38. King A., Phillips I. 2001; The in vitro activity of daptomycin against 514 Gram-positive aerobic clinical isolates. J Antimicrob Chemother 48:219–223 [CrossRef]
    [Google Scholar]
  39. Kleinkauf H., Von Dohren H. 1996; A nonribosomal system of peptide biosynthesis. Eur J Biochem 236:335–351 [CrossRef]
    [Google Scholar]
  40. Kohli R. M., Walsh C. T. 2003; Enzymology of acyl chain macrocyclization in natural product biosynthesis. Chem Commun 3:297–307
    [Google Scholar]
  41. Kreuzman A. J., Hodges R. L., Swartling J. R., Pohl T. E., Ghag S. K., Baker P. J., McGilvray D., Yeh W. K. 2000; Membrane-associated echinocandin B deacylase of Actinoplanes utahensis: purification, characterization, heterologous cloning and enzymatic deacylation reaction. J Ind Microbiol Biotechnol 24:173–180 [CrossRef]
    [Google Scholar]
  42. Kuhstoss S., Rao R. N. 1991; Analysis of the integration function of the streptomycete bacteriophage πC31. J Mol Biol 222:897–908 [CrossRef]
    [Google Scholar]
  43. Lauer B., Russwurm R., Schwarz W., Kalmanczhelyi A., Bruntner C., Rosemeier A., Bormann C. 2001; Molecular characterization of co-transcribed genes from Streptomyces tendae Tu901 involved in the biosynthesis of the peptidyl moiety and assembly of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 264:662–673 [CrossRef]
    [Google Scholar]
  44. Linne U., Doekel S., Marahiel M. A. 2001; Portability of epimerization domain and role of peptidyl carrier protein on epimerization activity in nonribosomal peptide synthetases. Biochemistry 40:15824–15834 [CrossRef]
    [Google Scholar]
  45. Marahiel M. A., Stachelhaus T., Mootz H. D. 1997; Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 97:2651–2674 [CrossRef]
    [Google Scholar]
  46. Marchler-Bauer A., Anderson J., DeWeese-Scott C. & 24 other authors; 2003; CDD: a curated Entrez database of conserved domain alignments. Nucleic Acids Res 31:383–387 [CrossRef]
    [Google Scholar]
  47. Marshall C. G., Burkart M. D., Meray R. K., Walsh C. T. 2002; Carrier protein recognition in siderophore-producing nonribosomal peptide synthetases. Biochemistry 41:8429–8437 [CrossRef]
    [Google Scholar]
  48. Martin R. G., Rosner J. L. 1995; Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences. Proc Natl Acad Sci U S A 92:5456–5460 [CrossRef]
    [Google Scholar]
  49. McHenney M. A., Baltz R. H. 1996; Gene transfer and transposition mutagenesis in Streptomyces roseosporus: mapping of insertions that influence daptomycin or pigment production. Microbiology 142:2363–2373 [CrossRef]
    [Google Scholar]
  50. McHenney M. A., Hosted T. J., Dehoff B. S., Rosteck P. R., Baltz R. H. 1998; Molecular cloning and physical mapping of the daptomycin gene cluster from Streptomyces roseosporus . J Bacteriol 180:143–151
    [Google Scholar]
  51. Mendez C., Salas J. A. 1998; ABC transporters in antibiotic-producing actinomycetes. FEMS Microbiol Lett 158:1–8 [CrossRef]
    [Google Scholar]
  52. Mootz H. D., Marahiel M. A. 1997; The tyrocidine biosynthesis operon of Bacillus brevis: complete nucleotide sequence and biochemical characterization of functional internal adenylation domains. J Bacteriol 179:6843–6850
    [Google Scholar]
  53. NCCLS 2003; Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Document M7:A6 Wayne, PA: National Committee for Clinical Laboratory Standards;
    [Google Scholar]
  54. Raibaud A., Zalacain M., Holt T. G., Tizard R., Thompson C. J. 1991; Nucleotide sequence analysis reveals linked N-acetyl hydrolase, thioesterase, transport, and regulatory genes encoded by the bialaphos biosynthetic gene cluster of Streptomyces hygroscopicus . J Bacteriol 173:4454–4463
    [Google Scholar]
  55. Saraste M., Sibbald P. R., Wittinghofer A. 1990; The P-loop – a common motif in ATP- and GTP-binding proteins. Trends Biochem Sci 15:430–434 [CrossRef]
    [Google Scholar]
  56. Schlumbohm W., Stein T., Ullrich C., Vater J., Krause M., Marahiel M. A., Kruft V., Wittmann-Liebold B. 1991; An active serine is involved in covalent substrate amino acid binding at each reaction center of gramicidin S synthetase. J Biol Chem 266:23135–23141
    [Google Scholar]
  57. Schneider A., Marahiel M. A. 1998; Genetic evidence for a role of thioesterase domains, integrated in or associated with peptide synthetases, in non-ribosomal peptide biosynthesis in Bacillus subtilis. Arch Microbiol 169:404–410 [CrossRef]
    [Google Scholar]
  58. Silverman J. A., Oliver N., Andrew T., Li T. 2001; Resistance studies with daptomycin. Antimicrob Agents Chemother 45:1799–1802 [CrossRef]
    [Google Scholar]
  59. Stachelhaus T., Mootz H. D., Marahiel M. A. 1999; The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem Biol 6:493–505 [CrossRef]
    [Google Scholar]
  60. Tally F. P., DeBruin M. F. 2000; Development of daptomycin for Gram-positive infections. J Antimicrob Chemother 46:523–526 [CrossRef]
    [Google Scholar]
  61. Tally F. P., Zechel M., Wasileski M. W., Carini C., Berman C. L., Drusano G. L., Oleson F. B. Jr 1999; Daptomycin: a novel agent for Gram-positive infections. Expert Opin Investig Drugs 8:1223–1238 [CrossRef]
    [Google Scholar]
  62. Weber G., Schorgendorfer K., Schneider-Scherzer E., Leitner E. 1994; The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45·8-kilobase open reading frame. Curr Genet 26:120–125 [CrossRef]
    [Google Scholar]
  63. Wessels P., von Döhren H., Kleinkauf H. 1996; Biosynthesis of acylpeptidolactones of the daptomycin type. A comparative analysis of peptide synthetases forming A21978C and A54145. Eur J Biochem 242:665–673 [CrossRef]
    [Google Scholar]
  64. Wise R., Andrews J. M., Ashby J. P. 2001; Activity of daptomycin against Gram-positive pathogens: a comparison with other agents and the determination of a tentative breakpoint. J Antimicrob Chemother 48:563–567 [CrossRef]
    [Google Scholar]
  65. Yeats C., Bentley S., Bateman A. 2003; New knowledge from old: in silico discovery of novel protein domains in Streptomyces coelicolor . BMC Microbiol 3: 3 [View Article] [CrossRef]
    [Google Scholar]
  66. Zeng X., Saxild H. H. 1999; Identification and characterization of a DeoR-specific operator sequence essential for induction of dra-nupC-pdp operon expression in Bacillus subtilis . J Bacteriol 181:1719–1727
    [Google Scholar]
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