Abstract
Nonomuraea strain ATCC 39727 produces the glycopeptide A40926, used for manufacturing dalbavancin, currently in advanced clinical trials. From the gene cluster involved in A40926 biosynthesis, a strain deleted in dbv23 was constructed. This mutant can produce only the glycopeptides lacking the O-linked acetyl residue at position 6 of the mannose moiety, while, under identical fermentation conditions, the wild-type strain produces mostly glycopeptides carrying an acetylated mannose. Furthermore, the total amount of glycopeptides produced by the mutant strain was found to be approximately twice that of the wild type. The reduced level of glycopeptides observed in the wild-type strain may be due to an inhibitory effect exerted by the acetylated compound on the biosynthesis of A40926. Indeed, spiking production cultures with ≥1 μg/ml of the acetylated glycopeptide inhibited A40926 production in the mutant strain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alduina R, Lo Piccolo L, D’Alia D, Ferraro C, Gunnarsson N, Donadio S, Puglia AM (2007) Phosphate-controlled regulator for the biosynthesis of the dalbavancin precursor A40926. J Bacteriol 189:8120–8129
Beltrametti F, Lazzarini A, Brunati C, Marazzi A, Jovetic S, Selva E, Marinelli F (2003) Production and characterization of monochlorinated and dechlorinated A40926 derivatives. J Antibiot 56:773–782
Beltrametti F, Jovetic S, Feroggio M, Gastaldo L, Selva E, Marinelli F (2004) Valine influences production and complex composition of glycopeptide antibiotic A40926 in fermentations of Nonomuraea sp. ATCC 39727. J Antibiot 57:37–44
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
Candiani G, Abbondi M, Borgonovi M, Romanò G, Parenti F (1999) In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother 44:179–192
Donadio S, Sosio M (2008) Biosynthesis of glycopeptides: prospects for improved antibacterials. Curr Top Med Chem 8:654–666
Donadio S, Sosio M, Stegmann E, Weber T, Wohlleben W (2005) Comparative analysis and insights into the evolution of gene clusters for glycopeptide antibiotic biosynthesis. Mol Genet Genomics 274:40–50
Goldstein BP, Selva E, Gastaldo L, Berti M, Pallanza R, Ripamonti F, Ferrari P, Denaro M, Arioli V, Cassani G (1987) A40926, a new glycopeptide antibiotic with anti-Neisseria activity. Antimicrob Agents Chemother 31:1961–1966
Hubbard BK, Walsh CT (2003) Vancomycin assembly: nature's way. Angew Chem Int Ed Engl 42:730–65
Jovetic S, Feroggio M, Marinelli F, Lancini G (2008) Factors influencing cell fatty acid composition and A40926 antibiotic complex production in Nonomuraea sp. ATCC 39727. J Ind Microbiol Biotech 35:1131–1138
Kominek LA (1975) Cycloheximide production by Streptomyces griseus: control mechanisms of cycloheximide biosynthesis. Antimicrob Agents Chemother 7:856–860
Kruger RG, Lu W, Oberthür M, Tao J, Kahne D, Walsh CT (2005) Tailoring of glycopeptide scaffolds by the acyltransferases from the teicoplanin and A-40, 926 biosynthetic operons. Chem Biol 12:131–140
Lancini GC (1989) Fermentation and biosynthesis of glycopeptide antibiotics. In: Bushell ME, Gräfe U (eds) Bioactive metabolites from microorganisms. Elsevier, Amsterdam, pp 283–296
Li YS, Ho JY, Huang CC, Lyu SY, Lee CY, Huang YT, Wu CJ, Chan HC, Huang CJ, Hsu NS, Tsai MD, Li TL (2007) A unique flavin mononucleotide-linked primary alcohol oxidase for glycopeptide A40926 maturation. J Am Chem Soc 129:13384–13385
Liu C-M, Hermann T, Miller PA (1977) Feedback inhibition of the synthesis of an antibiotic: aurodox (X-5108). J Antibiot 30:244–251
Malabarba A, Ciabatti R, Scotti R, Goldstein BP, Ferrari P, Kurz M, Andreini BP, Denaro M (1995) New semisynthetic glycopeptides MDL 63, 246 and MDL 63, 042, and other amide derivatives of antibiotic A-40, 926 active against highly glycopeptide-resistant VanA enterococci. J Antibiot 48:869–883
Malik VS, Vining LC (1972) Effect of chloramphenicol on its biosynthesis by Streptomyces species 3022a. Can J Microbiol 18:137–143
Nicolaou KC, Boddy CN, Bräse S, Winssinger N (1999) Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew Chem Int Ed 38:2096–2152
Roecker AM, Pope SD (2008) Dalbavancin: a lipoglycopeptide antibacterial for Gram-positive infections. Expert Opin Pharmacother 9:1745–1754
Sosio M, Donadio S (2006) Understanding and manipulating glycopeptide pathways: the example of the dalbavancin precursor A40926. J Ind Microbiol Biotech 33:569–576
Sosio M, Stinchi S, Beltrametti F, Lazzarini A, Donadio S (2003) The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by Nonomuraea species. Chem Biol 10:541–549
Stinchi S, Azimonti S, Donadio S, Sosio M (2003) A gene transfer system for the glycopeptide producer Nonomuraea sp. ATCC39727. FEMS Microbiol Lett 225:53–57
Stinchi S, Carrano L, Lazzarini A, Feroggio M, Grigoletto A, Sosio M, Donadio S (2006) A derivative of the glycopeptide A40926 produced by inactivation of the beta-hydroxylase gene in Nonomuraea sp. ATCC39727. FEMS Microbiol Lett 256:229–235
Technikova-Dobrova Z, Damiano F, Tredici SM, Vigliotta G, di Summa R, Palese L, Abbrescia A, Labonia N, Gnoni GV, Alifano P (2004) Design of mineral medium for growth of Actinomadura sp. ATCC 39727, producer of the glycopeptide A40926: effects of calcium ions and nitrogen sources. Appl Microbiol Biotechnol 65:671–677
Toropova EG, Egorov NS, Egorova OA, Suchkova LA (1973) Effect of ristomycin and excess of orthophosphate in a medium on the growth of Proactinomyces fructiferi var. ristomycini, production of organic acids and antibiotic biosynthesis. Antibiotiki 18:3–6
Waltho JP, Williams DH, Selva E, Ferrari P (1987) Structure elucidation of the glycopeptide antibiotic complex A40926. J Chem Soc Perkin Trans 1:2103–2107
Zerilli LF, Edwards DM, Borghi A, Gallo GG, Selva E, Denaro M, Lancini GC (1992) Determination of the acyl moieties of the antibiotic complex A40926 and their relation with the membrane lipids of the producer strain. Rapid Commun Mass Spectrom 6:109–114
Zou Y, Brunzelle JS, Nair SK (2008) Crystal structures of lipoglycopeptide antibiotic deacetylases: implications for the biosynthesis of A40926 and teicoplanin. Chem Biol 15:533–545
Acknowledgements
We are grateful to Richard White and Romeo Ciabatti for encouraging this project during difficult times and to Sonia Maffioli for helpful advice.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sosio, M., Canavesi, A., Stinchi, S. et al. Improved production of A40926 by Nonomuraea sp. through deletion of a pathway-specific acetyltransferase. Appl Microbiol Biotechnol 87, 1633–1638 (2010). https://doi.org/10.1007/s00253-010-2579-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-010-2579-2