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Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster

Abstract

In the ongoing effort to unlock the chemical potential of marine bacteria, genetic engineering of biosynthetic gene clusters (BGCs) is increasingly used to awake or improve expression of biosynthetic genes that may lead to discovery of novel bioactive natural products. Previously, we reported the successful capture, engineering and heterologous expression of an orphan BGC from the marine actinomycete Saccharomonospora sp. CNQ-490, which resulted in the isolation of the novel lipopeptide antibiotic taromycin A. Herein we report the isolation and structure elucidation of taromycin B, the second most abundant product of the taromycin biosynthetic series, and show that taromycins A and B exhibit complex chromatographic properties indicative of interconverting conformations. Taromycins A and B display potent activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium clinical isolates, suggestive that the taromycin molecular scaffold is a promising starting point for further derivatization to produce compounds with promising antibiotic characteristics.

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References

  1. Heinemann, B., Kaplan, M. A., Muir, R. D. & Hooper, I. R. Amphomycin, a new antibiotic. Antibiot. Chemother. 3, 1239–1242 (1953).

    CAS  Google Scholar 

  2. Tanaka, H., Oiwa, R., Matsukura, S., Inokoshi, J. & Omura, S. Studies on bacterial cell wall inhibitors. X. Properties of phospho-N-acetylmuramoyl-pentapeptide-transferase in peptidoglycan synthesis of Bacillus megaterium and its inhibition by amphomycin. J. Antibiot. 35, 1216–1221 (1982).

    CAS  Article  Google Scholar 

  3. Yang, H.-J. et al. Two novel amphomycin analogues from Streptomyces canus strain FIM-0916. Nat. Prod. Res. 28, 861–867 (2014).

    CAS  Article  Google Scholar 

  4. Eisenstein, B. I., Oleson, F. B. Jr. & Baltz, R. H. Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD. Clin. Infect. Dis. 50, S10–S15 (2010).

    CAS  Article  Google Scholar 

  5. Mnif, I. & Ghribi, D. Review lipopeptides biosurfactants: mean classes and new insights for industrial, biomedical, and environmental applications. Biopolymers 104, 129–147 (2015).

    CAS  Article  Google Scholar 

  6. Ball, L.-J. et al. NMR structure determination and calcium binding effects of lipopeptide antibiotic daptomycin. Org. Biomol. Chem. 2, 1872–1878 (2004).

    CAS  Article  Google Scholar 

  7. Micklefield, J. Biosynthesis and biosynthetic engineering of calcium-dependent lipopeptide antibiotics. Pure Appl. Chem. 81, 1065–1074 (2009).

    CAS  Article  Google Scholar 

  8. Yamanaka, K. et al. Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc. Natl Acad. Sci. 111, 1957–1962 (2014).

    CAS  Article  Google Scholar 

  9. Debono, M. et al. Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032). J. Antibiot. 41, 1093–1105 (1988).

    CAS  Article  Google Scholar 

  10. Huber, F. M., Pieper, R. L. & Tietz, A. J. The formation of daptomycin by supplying decanoic acid to Streptomyces roseosporus cultures producing the antibiotic complex A21978C. J. Biotechnol. 7, 283–292 (1988).

    CAS  Article  Google Scholar 

  11. Gu, J. Q. et al. Structural characterization of a lipopeptide antibiotic A54145E(Asn3Asp9) produced by a genetically engineered strain of Streptomyces fradiae. J. Antibiot. 64, 111–116 (2011).

    CAS  Article  Google Scholar 

  12. Agarwal, V., Lin, S., Lukk, T., Nair, S. K. & Cronan, J. E. Structure of the enzyme-acyl carrier protein (ACP) substrate gatekeeper complex required for biotin synthesis. Proc. Natl Acad. Sci. 109, 17406–17411 (2012).

    CAS  Article  Google Scholar 

  13. Cryle, M. J. & Schlichting, I. Structural insights from a P450 Carrier Protein complex reveal how specificity is achieved in the P450BioI ACP complex. Proc. Natl Acad. Sci. 105, 15696–15701 (2008).

    CAS  Article  Google Scholar 

  14. Li, Q. et al. Deciphering the biosynthetic origin of L-allo-isoleucine. J. Am. Chem. Soc. 138, 408–415 (2016).

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to PR Jensen and W Fenical for providing Saccharomonospora sp. CNQ-490, M Bibb for S. coelicolor M1146, RD Kersten for assistance with MS analysis, BM Dungan for assistance with NMR, X Tang and PA Jordan for helpful discussions. This work was supported by grants from the National Institutes of Health (R01-GM085770 to BSM, U01-AI124316 to VN and Instrument Grant S10-OD010640).

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Correspondence to Bradley S Moore.

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Supplementary Information accompanies the paper on The Journal of Antibiotics website

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Reynolds, K., Luhavaya, H., Li, J. et al. Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster. J Antibiot 71, 333–338 (2018). https://doi.org/10.1038/ja.2017.146

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