Abstract
Daptomycin and the A21978C antibiotic complex are lipopeptides produced by Streptomyces roseosporus and also in recombinant Streptomyces lividans TK23 and TK64 strains, when a 128 kbp region of cloned S. roseosporus DNA containing the daptomycin gene cluster is inserted site-specifically in the ϕC31 attB site. A21978C fermentation yields were initially much lower in S. lividans than in S. roseosporus, and detection was complicated by the production of host metabolites. However A21978C production in S. lividans was improved by deletion of genes encoding the production of actinorhodin and by medium optimization to control the chemical form of the calcium dependent antibiotic (CDA). This latter compound has not previously been chemically characterized as a S. lividans product. Adding phosphate to a defined fermentation medium resulted in formation of only the phosphorylated forms of CDA, which were well separated from A21978C on chromatographic analysis. Adjusting the level of phosphate in the medium led to an improvement in A21978C yield from 20 to 55 mg/l.
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References
Bibb MJ, Janssen GR, Ward JM (1985) Cloning and analysis of the promoter region of the erythromycin resistance gene (ermE) of Streptomyces erythraeus. Gene 38:215–226
Bierman M, Logan R, O’Brien K, Seno ET, Rao RN, Schoner BE (1992) Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp . Gene 116:43–49
Chouayekh H, Virolle M-J (2002) The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans. Mol Microbiol 43:919–930
Debono M, Barnhart M, Carrell CB, Hoffman JA, Occolowitz JL, Abbott BJ, Fukuda DS, Hamill RL (1987) A21978C, a complex of new acidic peptide antibiotics: isolation, chemistry, and mass spectral structure elucidation. J Antibiot 40:761–777
Debono M, Abbott BJ, Molloy RM, Fukuda DS, Hunt AH, Daupert VM, Counter FT, Ott JL, Carrell CB, Howard LC, Boeck LD, Hamill RL (1988) Enzymatic and chemical modifications of lipopetide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032). J Antibiot 41:1093–1105
Eisenstein BI (2004) Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections. Expert Opin Investig Drugs 13:1159–1169
Gorst-Allman CP, Rudd BAM, Chang C, Floss HG (1981) Biosynthesis of actinorhodin. Determination of the point of dimerization. J Org Chem 46:455–456
Hojati Z, Milne C, Harvey B, Gordon L, Borg M, Flett F, Wilkinson B, Sidebottom PJ, Rudd BAM, Hayes MA, Smith CP, Micklefield J (2002) Structure, biosynthetic origin, and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor. Chem Biol 9:1–13
Hu H, Zhang Q, Ochi K (2002) Activation of antibiotic biosynthesis by specified mutations in the rpoB gene (encoding the RNA polymerase β subunit) of Streptomyces lividans. J Bacteriol 184:3984–3991
Huber FM, Pieper RL, Tietz AJ (1988) The formation of daptomycin by supplying decanoic acid to Streptomyces roseosporus cultures producing the antibiotic complex A21978C. J Biotechnol 7:283–292
Jung D, Rozek A, Okon M, Hancock REW (2004) Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chem Biol 11:949–957
Keiser T, Bibb M, Buttner MJ, Chater KF, Hopwood D (2000) Practical Streptomycete genetics. John Innes Foundation, Norwich
Kempter C, Kaiser D, Haag S, Nicholson G, Gnau V, Walk T, Gierling KH, Decker H, Zahner H, Jung G, Metzger JW (1997) CDA: calcium-dependent peptide antibiotics from Streptomyces coelicolor A3(2) containing unusual residues. Angew Chem Int Ed Engl 36:498–501
LaPlante KL, Rybak MJ (2004) Daptomycin – a novel antibiotic against Gram-positive pathogens. Expert Opin Pharmacother 5:2321–2331
Malpartida F, Hopwood DA (1984) Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature 309: 462–464
Malpartida F, Hopwood DA (1986) Physical and genetic characterisation of the gene cluster for the antibiotic actinorhodin in Streptomyces coelicolor A3(2). Mol Gen Genet 205:66–73
Miao V, Coeffet-LeGal M-F, Brian P, Brost R, Penn J, Whiting A, Martin S, Ford R, Parr I, Bouchard M, Silva CJ, Wrigley SK, Baltz RH (2005) Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 151:1507–1523
Raja A, LaBonte J, Lebbos J, Kirkpatrick P (2003) Fresh from the pipeline: daptomycin. Nat Rev Drug Disc 2:943–944
Shima J, Hesketh A, Okamoto S, Kawamoto S, Ochi K (1996) Induction of actinorhodin production by rpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3(2). J Bacteriol 178:7276–7284
Silverman JA, Perlmutter NG, Shapiro HM (2003) Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agent Chemother 47:2538–2544
Zeeck A, Christiansen P (1969). Konformation and Konfiguration des Actinorhodins. Liebigs Ann Chem 724:172–182
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Penn, J., Li, X., Whiting, A. et al. Heterologous production of daptomycin in Streptomyces lividans . J IND MICROBIOL BIOTECHNOL 33, 121–128 (2006). https://doi.org/10.1007/s10295-005-0033-8
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DOI: https://doi.org/10.1007/s10295-005-0033-8