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Conglobatins B–E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin

The Journal of Antibiotics volume 73, pages 756–765 (2020)Cite this article

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Abstract

Chemical investigation of a previously unreported indigenous Australian Streptomyces strain MST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, Streptomyces conglobatus ATCC 31005. Conglobatins B–E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC50 0.084, 1.05 and 0.45 µg ml−1, respectively) compared with conglobatin (IC50 1.39 µg ml−1).

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References

  1. Brockmann H, Henkel W. Pikromycin, ein neues Antibiotikum aus Actinomyceten. Naturwissenschaften. 1950;37:138–9.

    Article  CAS  Google Scholar 

  2. Omura S. Macrolide antibiotics: chemistry, biology, and practice. 2nd ed. San Diego: Academic Press; 2002.

  3. Kamal A, Hahn G. 106. Chaksine. Part I. J Chem Soc. 1958;80:555–7.

  4. Polborn KSW, Connolly JD, Huneck S. Structure of the macrocycle bis-lactone lepranthin from the lichen Arthonia impolita; an X-ray analysis. Z Naturforsch. 1995;50b:1111–4.

    Article  Google Scholar 

  5. Kis Z, Furger P, Sigg H. Über die Isolierung von Pyrenophorol. Cell Mol Life Sci. 1969;25:123–4.

    Article  CAS  Google Scholar 

  6. Fuska J, Ivanitskaya L, Horakova K, Kuhr I. The cytotoxic effects of a new antibiotic vermiculine. J Antibiot. 1974;27:141–2.

    Article  CAS  Google Scholar 

  7. Kind R, Zeeck A, Grabley S, Thiericke R, Zerlin M. Secondary metabolites by chemical screening. 30. Helmidiol, a new macrodiolide from Alternaria alternata. J Nat Prod. 1996;59:539–40.

    Article  CAS  Google Scholar 

  8. Kaiser H, Keller-Schierlein W. Stoffwechselprodukte von mikroorganismen. 202. Mitteilung. Strukturaufklärung von elaiophylin: Spektroskopische untersuchungen und abbau. Helv Chim. 1981;64:407–24.

    Article  CAS  Google Scholar 

  9. Klassen JL, Lee SR, Thomas-Poulsen M, Beemelmanns C, Kim KH. Efomycins K and L from a termite-associated Streptomyces sp. M56 and their putative biosynthetic origin. Front Microbiol. 2019;10:1739.

    Article  Google Scholar 

  10. Nakakoshi M, Kimura K-I, Nakajima N, Yoshihama M, Uramoto M. SNA-4606-1, a new member of elaiophylins with enzyme inhibition activity against testosterone 5 α-reductase. J Antibiot. 1999;52:175–7.

    Article  CAS  Google Scholar 

  11. Yamada T, Kikuchi T, Tanaka R, Numata A. Halichoblelides B and C, potent cytotoxic macrolides from a Streptomyces species separated from a marine fish. Tetrahedron Lett. 2012;53:2842–6.

    Article  CAS  Google Scholar 

  12. Yamada T, Minoura K, Numata A. Halichoblelide, a potent cytotoxic macrolide from a Streptomyces species separated from a marine fish. Tetrahedron Lett. 2002;43:1721–4.

    Article  CAS  Google Scholar 

  13. Westley JW, Liu C-M, Evans RH, Blount JF. Conglobatin, a novel macrolide dilactone from Streptomyces conglobatus ATCC 31005. J Antibiot. 1979;32:874–7.

    Article  CAS  Google Scholar 

  14. Hashida J, Niitsuma M, Iwatsuki M, Mori M, Ishiyama A, Namatame M, et al. Panowamycins A and B, new antitrypanosomal isochromans produced by Streptomyces sp. K07-0010. J Antibiot. 2012;65:197–202.

    Article  CAS  Google Scholar 

  15. Huang W, Ye M, Zhang L, Wu Q, Zhang M, Xu J, et al. FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation. Mol Cancer. 2014;13:150.

    Article  Google Scholar 

  16. Otoguro K, Iwatsuki M, Ishiyama A, Namatame M, Nishihara-Tsukashima A, Sato S, et al. In vitro and in vivo antiprotozoal activities of bispolides and their derivatives. J Antibiot. 2010;63:275–7.

    Article  CAS  Google Scholar 

  17. Zhou Y, Murphy AC, Samborskyy M, Prediger P, Dias LC, Leadlay PF. Iterative mechanism of macrodiolide formation in the anticancer compound conglobatin. Chem Biol. 2015;22:745–54.

    Article  CAS  Google Scholar 

  18. Lacey HJ, Gilchrist CL, Crombie A, Kalaitzis JA, Vuong D, Rutledge PJ, et al. Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis. Beilstein J Org Chem. 2019;15:2631–43.

    Article  CAS  Google Scholar 

  19. Lacey HJ, Vuong D, Pitt JI, Lacey E, Piggott AM. Kumbicins A–D: bis-indolyl benzenoids and benzoquinones from an Australian soil fungus, Aspergillus kumbius. Aust J Chem. 2016;69:152–60.

    Article  CAS  Google Scholar 

  20. Li H, Gilchrist CL, Lacey HJ, Crombie A, Vuong D, Pitt JI, et al. Discovery and heterologous biosynthesis of the burnettramic acids: rare PKS-NRPS-derived bolaamphiphilic pyrrolizidinediones from an Australian Fungus, Aspergillus burnettii. Org Lett. 2019;21:1287–91.

    Article  CAS  Google Scholar 

  21. Lacey E, Tennant S. Secondary metabolites: the focus of biodiscovery and perhaps the key to unlocking new depths in taxonomy. Microbiol Aust. 2003;24:34–5.

    Article  Google Scholar 

  22. Klindworth A, Pruesse E, Schweer T, Peplies J, Quast C, Horn M, et al. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res. 2013;41:e1.

    Article  CAS  Google Scholar 

  23. Sievers F, Higgins DG. Clustal Omega, accurate alignment of very large numbers of sequences. Methods Mol Biol. 2014;1079:105–16.

  24. Labeda D, Goodfellow M, Brown R, Ward A, Lanoot B, Vanncanneyt M, et al. Phylogenetic study of the species within the family Streptomycetaceae. Antonie Van Leeuwenhoek. 2012;101:73–104.

    Article  CAS  Google Scholar 

  25. Price MN, Dehal PS, Arkin AP. FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS ONE. 2010;5:e9490.

    Article  Google Scholar 

  26. Letunic I, Bork P. Interactive tree of life (ITOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 2016;44:W242–5.

    Article  CAS  Google Scholar 

  27. Williams S, Goodfellow M, Alderson G, Wellington E, Sneath P, Sackin M. Numerical classification of Streptomyces and related genera. Microbiology. 1983;129:1743–813.

    Article  CAS  Google Scholar 

  28. Spížek J, Málek I, Doležilová L, Vondráček M, Vaněk Z. Metabolites of Streptomyces noursei. Folia Microbiol. 1965;10:259–62.

    Article  Google Scholar 

  29. Sujarit K, Kudo T, Ohkuma M, Pathom-Aree W, Lumyong S. Streptomyces palmae sp. nov., isolated from oil palm (Elaeis guineensis) rhizosphere soil. Int J Syst Evol Microbe. 2016;66:3983–8.

    Article  CAS  Google Scholar 

  30. Schregenberger C, Seebach D. Synthesis and determination of the absolute configuration of the macrodiolide (+)-conglobatin. Tetrahedron Lett. 1984;25:5881–4.

    Article  CAS  Google Scholar 

  31. Huang W, Wu Q-d, Zhang M, Kong Y-L, Cao P-R, Zheng W, et al. Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib. Cancer Lett. 2015;356:862–71.

    Article  CAS  Google Scholar 

  32. Dramae A, Nithithanasilp S, Choowong W, Rachtawee P, Prabpai S, Kongsaeree P, et al. Antimalarial 20-membered macrolides from Streptomyces sp. BCC33756. Tetrahedron. 2013;69:8205–8.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr John Kalaitzis (MQ) for acquisition of NMR data and Dr Matthew McKay (MQ) for acquisition of HRMS data. Heather Lacey is the recipient of an Australian Government Research Training Program Scholarship. This research was funded, in part, by the Australian Research Council (FT130100142, FT160100233) and the Cooperative Research Centres Projects scheme (CRCPFIVE000119).

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Authors and Affiliations

  1. Microbial Screening Technologies, Smithfield, Sydney, NSW, 2164, Australia

    Heather J. Lacey, Daniel Vuong & Ernest Lacey

  2. School of Chemistry, The University of Sydney, Camperdown, Sydney, NSW, 2006, Australia

    Heather J. Lacey & Peter J. Rutledge

  3. School of Molecular Sciences, The University of Western Australia, Crawley, Perth, WA, 6009, Australia

    Thomas J. Booth & Yit-Heng Chooi

  4. Department of Molecular Sciences, Macquarie University, North Ryde, Sydney, NSW, 2109, Australia

    Ernest Lacey & Andrew M. Piggott

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  1. Heather J. Lacey
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Correspondence to Heather J. Lacey.

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Lacey, H.J., Booth, T.J., Vuong, D. et al. Conglobatins B–E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin. J Antibiot 73, 756–765 (2020). https://doi.org/10.1038/s41429-020-0332-3

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