Note

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

Received:
Revised:
Accepted:
Published online:

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.

  • Subscribe to The Journal of Antibiotics for full access:

    $305

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , , & Amphomycin, a new antibiotic. Antibiot. Chemother. 3, 1239–1242 (1953).

  2. 2.

    , , , & 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).

  3. 3.

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

  4. 4.

    , & Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD. Clin. Infect. Dis. 50, S10–S15 (2010).

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

    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).

  9. 9.

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

  10. 10.

    , & The formation of daptomycin by supplying decanoic acid to Streptomyces roseosporus cultures producing the antibiotic complex A21978C. J. Biotechnol. 7, 283–292 (1988).

  11. 11.

    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).

  12. 12.

    , , , & Structure of the enzyme-acyl carrier protein (ACP) substrate gatekeeper complex required for biotin synthesis. Proc. Natl Acad. Sci. 109, 17406–17411 (2012).

  13. 13.

    & 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).

  14. 14.

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

Download references

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).

Author information

Author notes

    • Kirk A Reynolds
    •  & Hanna Luhavaya

    KA Reynolds and H Luhavaya contributed equally to this work.

    • Kazuya Yamanaka

    Current address: Department of Life Science and Biotechnology, Kansai University, Suita, Osaka, Japan.

Affiliations

  1. Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA, USA

    • Kirk A Reynolds
    • , Hanna Luhavaya
    • , Jie Li
    • , Kazuya Yamanaka
    •  & Bradley S Moore
  2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA

    • Kirk A Reynolds
  3. Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA

    • Samira Dahesh
    •  & Victor Nizet
  4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA, USA

    • Victor Nizet
    •  & Bradley S Moore

Authors

  1. Search for Kirk A Reynolds in:

  2. Search for Hanna Luhavaya in:

  3. Search for Jie Li in:

  4. Search for Samira Dahesh in:

  5. Search for Victor Nizet in:

  6. Search for Kazuya Yamanaka in:

  7. Search for Bradley S Moore in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Bradley S Moore.

Supplementary information

Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)