Abstract
A novel sansanmycin analogue, sansanmycin Q (1), was identified by genome mining from the fermentation broth of Streptomyces sp. SS (CPCC 200442). In comparison with other sansanmycin compounds, sansanmycin Q has an extra glycine residue at the N-terminus of the pseudopeptide backbone. The additional glycine was proved to be assembled to sansanmycin A by SsaB, a tRNA-dependent aminoacyltransferase, based on the results of rescrutiny of sansanmycin biosynthetic gene cluster, and then overexpression and knockout of ssaB in the wild-type strain. The structure of sansanmycin Q was assigned by interpretation of NMR and mass spectral data. The results of the bioassay disclosed that sansanmycin Q exhibited more potency against Mycobacterium tuberculosis H37Rv and a rifampicin- and isoniazid-resistant strain than sansanmycin A.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Xie Y, Chen R, Si S, Sun C, Xu H. A new nucleosidyl-peptide antibiotic, sansanmycin. J Antibiot. 2007;60:158–61.
Xie Y, et al. NRPS substrate promiscuity leads to more potent antitubercular sansanmycin analogues. J Nat Prod. 2014;77:1744–8.
Fronko RM, Lee JC, Galazzo JG, Chamberland S, Malouin F, Lee MD. New pacidamycins produced by Streptomyces coeruleorubidus, NRRL 18370. J Antibiot. 2000;53:1405–10.
Chen RH, Buko AM, Whittern DN, McAlpine JB. Pacidamycins, a novel series of antibiotics with anti-Pseudomonas aeruginosa activity. II. Isolation and structural elucidation. J Antibiot. 1989;42:512–20.
Isono F, Sakaida Y, Takahashi S, Kinoshita T, Nakamura T, Inukai M, Mureidomycins E. and F, minor components of mureidomycins. J Antibiot. 1993;46:1203–7.
Isono F, Inukai M, Takahashi S, Haneishi T, Kinoshita T, Kuwano H, Mureidomycins A-D. novel peptidylnucleoside antibiotics with spheroplast forming activity. II. Structural elucidation. J Antibiot. 1989;42:667–73.
Chatterjee S, et al. Napsamycins, new Pseudomonas active antibiotics of the mureidomycin family from Streptomyces sp. HIL Y-82,11372. J Antibiot. 1994;47:595–8.
Isono F, Inukai M. Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis. Antimicrob Agents Chemother. 1991;35:234–6.
Fernandes PB, et al. Pacidamycins, a novel series of antibiotics with anti-Pseudomonas aeruginosa activity. III. Microbiologic profile. J Antibiot. 1989;42:521–6.
Isono F, Katayama T, Inukai M, Haneishi T, Mureidomycins A-D. novel peptidylnucleoside antibiotics with spheroplast forming activity. III. Biological properties. J Antibiot. 1989;42:674–9.
Rackham EJ, Gruschow S, Ragab AE, Dickens S, Goss RJ. Pacidamycin biosynthesis: identification and heterologous expression of the first uridyl peptide antibiotic gene cluster. Chembiochem. 2010;11:1700–9.
Zhang W, Ostash B, Walsh CT. Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics. Proc Natl Acad Sci USA. 2010;107:16828–33.
Zhang W, et al. Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. J Am Chem Soc. 2011;133:5240–3.
Kaysser L, et al. Identification of a napsamycin biosynthesis gene cluster by genome mining. Chembiochem. 2011;12:477–87.
Li Q, Wang L, Xie Y, Wang S, Chen R, Hong B. SsaA, a member of a novel class of transcriptional regulators, controls sansanmycin production in Streptomyces sp. strain SS through a feedback mechanism. J Bacteriol. 2013;195:2232–43.
Wang L, et al. Draft genome sequence of Streptomyces sp. strain SS, which produces a series of uridyl peptide antibiotic sansanmycins. J Bacteriol. 2012;194:6988–9.
Zhang W, Ntai I, Kelleher NL, Walsh CT. tRNA-dependent peptide bond formation by the transferase PacB in biosynthesis of the pacidamycin group of pentapeptidyl nucleoside antibiotics. Proc Natl Acad Sci USA. 2011;108:12249–53.
Xie Y, Xu H, Si S, Sun C, Chen R. Sansanmycins B and C, new components of sansanmycins. J Antibiot. 2008;61:237–40.
Xie Y, Xu H, Sun C, Yu Y, Chen R. Two novel nucleosidyl-peptide antibiotics: sansanmycin F and G produced by Streptomyces sp SS. J Antibiot. 2010;63:143–6.
Shi Y, et al. Improving the N-terminal diversity of sansanmycin through mutasynthesis. Microb cell Factor. 2016;15:77.
Zhang N, et al. Precursor-directed biosynthesis of new sansanmycin analogs bearing para-substituted-phenylalanines with high yields. J Antibiot. 2016;69:765–8.
Alva V, Nam SZ, Soding J, Lupas AN. The MPI bioinformatics toolkit as an integrative platform for advanced protein sequence and structure analysis. Nucleic Acids Res. 2016;44:W410–5.
Biarrotte-Sorin S, Maillard AP, Delettre J, Sougakoff W, Arthur M, Mayer C. Crystal structures of Weissella viridescens FemX and its complex with UDP-MurNAc-pentapeptide: insights into FemABX family substrates recognition. Structure. 2004;12:257–67.
Benson TE, et al. X-ray crystal structure of Staphylococcus aureus FemA. Structure. 2002;10:1107–15.
Neuwald AF, Landsman D. GCN5-related histone N-acetyltransferases belong to a diverse superfamily that includes the yeast SPT10 protein. Trends Biochem Sci. 1997;22:154–5.
Vetting MW, et al. Structure and functions of the GNAT superfamily of acetyltransferases. Arch Biochem Biophys. 2005;433:212–26.
Jiang L, et al. Identification of novel mureidomycin analogues via rational activation of a cryptic gene cluster in Streptomyces roseosporus NRRL 15998. Sci Rep. 2015;5:14111.
Tang X, Gross M, Xie Y, Kulik A, Gust B. Identification of mureidomycin analogues and functional analysis of an N-acetyltransferase in napsamycin biosynthesis. Chembiochem. 2013;14:2248–55.
Hong B, Phornphisutthimas S, Tilley E, Baumberg S, McDowall KJ. Streptomycin production by Streptomyces griseus can be modulated by a mechanism not associated with change in the adpA component of the A-factor cascade. Biotechnol Lett. 2007;29:57–64.
Boojamra CG, et al. Stereochemical elucidation and total synthesis of dihydropacidamycin D, a semisynthetic pacidamycin. J Am Chem Soc. 2001;123:870–4.
Li YB, et al. Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives. Bioorg Med Chem Lett. 2011;21:6804–7.
Tran AT, et al. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nat Commun. 2017;8:14414.
Acknowledgements
We acknowledge financial support from the Drug Innovation Major Project (2018ZX09711001-006-011 and 2018ZX09711001-007-001), the National Natural Science Foundation of China (81803410, 81872780, 81273415, 81603007, 81630089 and 81621064), CAMS Innovation Fund for Medical Sciences (2016-I2M-3-012, 2016-I2M-2-002 and 2018-I2M-3-005), Beijing Natural Science Foundation (7172137 and 7184227), the Fundamental Research Funds for the Central Universities (3332018095) and Institute of Medicinal Biotechnology Foundation (2016ZX350045 and 2016ZX350053).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
41429_2019_210_MOESM1_ESM.docx
Rescrutiny of the sansanmycin biosynthetic gene cluster leads to the discovery of a novel sansanmycin analogue with more potency against Mycobacterium tuberculosis
Rights and permissions
About this article
Cite this article
Shi, Y., Wang, X., He, N. et al. Rescrutiny of the sansanmycin biosynthetic gene cluster leads to the discovery of a novel sansanmycin analogue with more potency against Mycobacterium tuberculosis. J Antibiot 72, 769–774 (2019). https://doi.org/10.1038/s41429-019-0210-z
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41429-019-0210-z
