Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Proansamycin B derivatives from the post-PKS modification gene deletion mutant of Amycolatopsis mediterranei S699

The Journal of Antibiotics volume 77, pages 278–287 (2024)Cite this article

Subjects

Abstract

Ten new proansamycin B congeners (1–10) together with one known (11) were isolated and characterized on the basis of 1D and 2D NMR spectroscopic and HRESIMS data from the Amycolatopsis mediterranei S699 ΔPM::rifR+rif-orf19 mutant. Compounds 8 and 9 featured with six-membered ring and five-membered ring hemiketal, respectively. Compounds 1, 2, and 9 displayed antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus), with the MIC (minimal inhibitory concentration) values of 64, 8, and 128 µg/mL, respectively. Compound 1 showed significant cytotoxicity against MDA-MB-231, HepG2 and Panc-1 cell lines with IC50 (half maximal inhibitory concentration) values of 2.3 ± 0.2, 2.5 ± 0.3 and 3.8 ± 0.5 μM, respectively.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Floss HG, Yu TW. Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev. 2005;105:621–32.

    Article  CAS  PubMed  Google Scholar 

  2. Kupchan SM, Komoda Y, Court WA, Thomas GJ, Smith RM, Karim A, et al. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J Am Chem Soc. 1972;94:1354–6.

    Article  CAS  PubMed  Google Scholar 

  3. Sasaki K, Rinehart KL Jr, Slomp G, Grostic MF, Olson EC. Geldanamycin. I. structure assignment. J Am Chem Soc. 1970;92:7591–3.

    Article  CAS  PubMed  Google Scholar 

  4. Kang Q, Shen Y, Bai L. Biosynthesis of 3,5-AHBA-derived natural products. Nat Prod Rep. 2012;29:243–63.

    Article  CAS  PubMed  Google Scholar 

  5. Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, et al. Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell. 2001;104:901–12.

    Article  CAS  PubMed  Google Scholar 

  6. Artsimovitch I, Vassylyeva MN, Svetlov D, Svetlov V, Perederina A, Igarashi N, et al. Allosteric modulation of the RNA polymerase catalytic reaction is an essential component of transcription control by rifamycins. Cell. 2005;122:351–63.

    Article  CAS  PubMed  Google Scholar 

  7. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998;79:3–29.

    Article  CAS  PubMed  Google Scholar 

  8. Siu GK, Zhang Y, Lau TC, Lau RW, Ho PL, Yew WW, et al. Mutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis. J Antimicrob Chemothe. 2011;66:730–3.

    Article  CAS  Google Scholar 

  9. Ye F, Zhao X, Shi Y, Hu Y, Ding Y, Lu C, et al. Deciphering the timing of naphthalenic ring formation in the Biosynthesis of 8-Deoxyrifamycins. Org Lett. 2023;25:6474–78.

    Article  CAS  PubMed  Google Scholar 

  10. Han TY, Zhang K, Tang GL, Zhou Q. Characterizing Post‐PKS Modifications of 16‐Demethyl‐rifamycin revealed two dehydrogenases diverting the aromatization mode of naphthalenic ring in ansamycin biosynthesis. Chin J Chem. 2022;10:9–15.

    CAS  Google Scholar 

  11. Ye F, Shi Y, Zhao S, Li Z, Wang H, Lu C, et al. 8-Deoxy-Rifamycin Derivatives from Amycolatopsis mediterranei S699 Delta rifT Strain. Biomolecules. 2020;10:1265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shi YR, Ye F, Song YL, Zhang XC, Lu CH, Shen YM. Rifamycin W Analogues from Amycolatopsis mediterranei S699 Delta rif-orf5 Strain. Biomolecules. 2021;11:920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu J, Wan E, Kim CJ, Floss HG, Mahmud T. Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. Microbioloogy. 2005;151:2515–28.

    CAS  Google Scholar 

  14. Qi F, Lei C, Li F, Zhang X, Wang J, Zhang W, et al. Deciphering the late steps of rifamycin biosynthesis. Nat Commun. 2018;9:2342.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Stratmann A, Schupp T, Toupet C, Schilling W, Oberer L, Traber R. New insights into rifamycin B biosynthesis: isolation of proansamycin B and 34a-deoxy-rifamycin W as early macrocyclic intermediates indicating two separated biosynthetic pathways. J Antibiot. 2002;55:396–406.

    Article  CAS  Google Scholar 

  16. Hutchinson CR, Floss HG. Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol. 1998;5:69–79.

    Article  PubMed  Google Scholar 

  17. Ghisalba O, Traxler P, Fuhrer H, Richter WJ. Early intermediates in the biosynthesis of ansamycins. II. Isolation and identification of proansamycin B-M1 and protorifamycin I-M1. J Antibiot. 1979;32:1267–72.

    Article  CAS  Google Scholar 

  18. Zhang J, Li S, Wu X, Guo Z, Lu C, Shen Y. Nam7 hydroxylase is responsible for the formation of the naphthalenic ring in the biosynthesis of neoansamycins. Org Lett. 2017;19:2442–45.

    Article  CAS  PubMed  Google Scholar 

  19. Zhou Q, Luo G-C, Zhang H, Tang G-L. 34a-Hydroxylation in Rifamycin biosynthesis catalyzed by cytochrome P450 encoded by rif-orf13. Chin J Org Chem. 2019;39:58–63.

    Article  Google Scholar 

  20. Shi Y, Zhang J, Tian X, Wu X, Li T, Lu C, et al. Isolation of 11,12-seco-Rifamycin W Derivatives Reveals a Cleavage Pattern of the Rifamycin Ansa Chain. Org Lett. 2019;21:900–03.

    Article  CAS  PubMed  Google Scholar 

  21. Li S, Lu C, Ou J, Deng J, Shen Y. Overexpression of hgc1 increases the production and diversity of hygrocins in Streptomyces sp. LZ35. RSC Adv. 2015;5:83843–46.

    Article  CAS  Google Scholar 

  22. Zhao GS, Li SR, Guo ZX, Sun MW, Lu CH. Overexpression of div8 increases the production and diversity of divergolides in Streptomyces sp W112. Rsc Adv. 2015;5:98209–14.

    Article  CAS  Google Scholar 

  23. Wang J, Li W, Wang H, Lu C. Pentaketide Ansamycin Microansamycins A-I from Micromonospora sp. Org Lett. 2018;20:1058–61.

    Article  CAS  PubMed  Google Scholar 

  24. Xiao YS, Zhang B, Zhang M, Guo ZK, Deng XZ, Shi J, et al. Rifamorpholines A–E, potential antibiotics from locust-associated actinobacteria Amycolatopsis sp. Hca4. Org Biomol Chem. 2017;15:3909–16.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was supported by the National Key Research and Development Program (2019YFA0905402), the National Natural Science Foundation of China (81673317, 81602979, 81530091), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_17R68).

Author information

Author notes

  1. These authors contributed equally: Xinyu Ma, Feng Ye

Authors and Affiliations

  1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, China

    Xinyu Ma, Feng Ye, Xiaochun Zhang, Zhan Li, Chunhua Lu & Yuemao Shen

  2. Department of Pharmacy, Shandong Second Provincial General Hospital, Jinan, Shandong, 250022, China

    Yanjiao Ding

  3. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China

    Yuemao Shen

  4. NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Shandong University, Jinan, Shandong, 250012, China

    Yuemao Shen

Authors
  1. Xinyu Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaochun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanjiao Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chunhua Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuemao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuemao Shen.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, X., Ye, F., Zhang, X. et al. Proansamycin B derivatives from the post-PKS modification gene deletion mutant of Amycolatopsis mediterranei S699. J Antibiot 77, 278–287 (2024). https://doi.org/10.1038/s41429-024-00708-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-024-00708-4

Search

Advanced search

Quick links