Brief Communication | Published:

Ala-geninthiocin, a new broad spectrum thiopeptide antibiotic, produced by a marine Streptomyces sp. ICN19

The Journal of Antibioticsvolume 72pages99105 (2019) | Download Citation

Abstract

Bioassay-guided screening of antibacterial compounds from the cultured marine Streptomyces sp. ICN19 provided Ala-geninthiocin (1), along with its known analogs geninthiocin (2) and Val-geninthiocin (3) and the indolocarbazole staurosporine (4). The structure of 1 was determined on the basis of 1D and 2D NMR spectra and ESI-HRMS. The absolute configurations of the amino acid residues were determined by enantioselective GC-MS analysis. Compound 1 exhibited potent activity against Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, Mycobacterium smegmatis, and Micrococcus luteus, as well as cytotoxicity against A549 human lung carcinoma cells with an IC50 value of 6 nM.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Raju R, Andrew MP, Zeinab K, Bernhardt PV, Capon RJ. Heronamycin A: a new benzothiazine ansamycin from an Australian marine-derived Streptomyces sp [J]. Tetrahedr Lett. 2012;53:1063–5.

  2. 2.

    Mullowney MW, et al. Diazaquinomycins E-G, novel diaza- anthracene analogs from a marine derived Streptomyces sp. Mar Drugs. 2014;12:3574–86.

  3. 3.

    Vicente J, et al. Monacyclinones, new angucyclinone metabolites isolated from Streptomyces sp. M7-15 associated with the Puerto Rican sponge Scopalina ruetzleri. Mar Drugs. 2015;13:4682–700.

  4. 4.

    Yun BS, Hidaka T, Furihata K, Seto H. Microbial metabolites with tipA promoter inducing activity. II. Geninthiocin, a novel thiopeptide produced by Streptomyces sp. DD84. J Antibiot. 1994;47:969–75.

  5. 5.

    Sajid I, Shaaban KA, Frauendorf H, Hasnain S, Laatsch HZ. Val- Geninthiocin: structure elucidation and MSn fragmentation of thiopeptide antibiotics produced by Streptomyces sp. RSF18. Z Naturforsch. 2008;B63:1223–30.

  6. 6.

    Schupp P, Proksch P, Wray V. Further new staurosporine derivatives from the ascidian Eudistoma toealensis and its predatory flatworm Pseudoceros sp. J Nat Prod. 2002;65:295–8.

  7. 7.

    Yun BS, Seto HPromoinducin. a novel thiopeptide produced by Streptomyces sp. SF2741. Biosci Biotech Biochem. 1995;59:876–80.

  8. 8.

    Abe H, Kushida K, Shiobara Y, Kodama M. The sutructures of sulfomycin I and berninamycin A. Tetrahedr Lett. 1988;29:1401–4.

  9. 9.

    Bowers AA, Waslch CT. Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus. J Am Chem Soc. 2010;132:12182–4.

  10. 10.

    Gescher A. Analogs of staurosporine: potential anticancer drugs? Gen Pharmac. 1998;31:721–8.

  11. 11.

    Porse BT, Leviev I, Mankin A, Garrett RA. The antibiotic thiostrepton inhibits a functional transition within protein L11 at the ribosomal GTPase centre. J Mol Biol. 1998;276:391–404.

  12. 12.

    Harms JM, et al. Translational regulation via L11: molecular switches on the ribosome turned on and off by thiostrepton and micrococcin. Mol Cell. 2008;30:26–38.

  13. 13.

    Zhang Q, Liu W. Biosynthesis of thiopeptide antibiotics and their pathway engineering. Nat Prod Rep. 2013;30:218–26.

  14. 14.

    Tamaoki T, et al. Staurosporine, a potent inhibitor of phospholipid/Ca kinase. Biochem Biophys Res Commun. 1986;135:397–402.

  15. 15.

    Bertrand R, Solary E, O’ Connor P, Kohn KW, Pommier Y. Induction of a common pathway of apoptosis by staurosporine. Exp Cell Res. 1994;211:314–21.

  16. 16.

    Hegde NS, Sanders DA, Rodriguez R, Balasubramanian S. The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem. 2011;3:725–31.

  17. 17.

    Gause GF, Preobrazhenskaya TP, Sveshnikova GV, Terekhova LP, Maksimova TS. A guide for determination of actinomycetes. Moscow: Nauka (in Russian); 1983.

Download references

Acknowledgements

The support of the Department of Science and Technology, Science and Engineering Research Board (DST-SERB), Govt. of India [F.No. SR/SO/HS-104/2012] to SGPV is gratefully acknowledged. The European Molecular Biology Organization (EMBO) is gratefully acknowledged for the Short term fellowship grant to AMI [ASTF No. 90 – 2016]. We thank Manfred Nimtz for the GC-MS analysis of amino acids. We thank Christel Kakosche, Romy Schade, and Wera Collisi for their excellent technical assistance.

Author information

Affiliations

  1. International Centre for Nanobiotechnology (ICN), Centre for Marine Science and Technology (CMST), Manonmaniam Sundaranar University, Rajakkamangalam-629502, Kanyakumari District, Tamil Nadu, India

    • Appadurai Muthamil Iniyan
    •  & Samuel Gnana Prakash Vincent
  2. Microbial Strain Collection, Helmholtz Centre for Infection Research GmbH (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany

    • Appadurai Muthamil Iniyan
    •  & Joachim Wink
  3. Department Microbial Drugs, Helmholtz Centre for Infection Research GmbH (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany

    • Enge Sudarman
  4. German Centre for Infection Research Association (DZIF), Partner site Hannover-Braunschweig, Inhoffenstrasse 7, 38124, Braunschweig, Germany

    • Enge Sudarman
    •  & Joachim Wink
  5. Molecular and Nanomedicine Research Unit, Centre for Nanoscience and Nanotechnology (CNSNT), Sathyabama Institute of Science and Technology, Jeppiaar Nagar, Chennai, 600119, TN, India

    • Rajaretinam Rajesh Kannan

Authors

  1. Search for Appadurai Muthamil Iniyan in:

  2. Search for Enge Sudarman in:

  3. Search for Joachim Wink in:

  4. Search for Rajaretinam Rajesh Kannan in:

  5. Search for Samuel Gnana Prakash Vincent in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Samuel Gnana Prakash Vincent.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41429-018-0115-2