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Halovirs I–K, antibacterial and cytotoxic lipopeptaibols from the plant pathogenic fungus Paramyrothecium roridum NRRL 2183

The Journal of Antibiotics volume 75, pages 247–257 (2022)Cite this article

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Abstract

Three new lipopeptaibols, halovirs I–K (1–3), were isolated from the solid culture of the phytopathogenic fungus Paramyrothecium roridum NRRL 2183. Their planar structures, which consist of a hexapeptide backbone and acyl substitutions at the N- and C-termini, were elucidated by comprehensive analysis of the 1D and 2D NMR spectroscopic data along with the detailed interpretation of the MS/MS fragmentation pattern. Absolute configurations of the amino acid/1,2-amino alcohol residues were determined using the advanced Marfey’s method. Bioinformatics analysis of the genome assembly of P. roridum NRRL 2183 revealed a gene cluster that is likely responsible for the biosynthesis of halovirs I–K. Analysis of the module and domain organization of the putative halovir synthetase PrHalA indicated that the assembly of 1–3 proceeds in an unconventional nonlinear fashion. 1 and 2 exhibited potent antibacterial activity against both antibiotic-sensitive and multidrug-resistant Gram-positive pathogens. These lipopeptaibols also displayed significant cytotoxicity toward human lung carcinoma A549, human breast carcinoma MCF-7, and human cervical carcinoma HeLa cells with IC50 values ranging from 1.3 to 3.3 μM.

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References

  1. Süssmuth RD, Mainz A. Nonribosomal peptide synthesis—principles and prospects. Angew Chem Int Ed. 2017;56:3770–821.

    Article  Google Scholar 

  2. Bills GF, et al. New insights into the echinocandins and other fungal non-ribosomal peptides and peptaibiotics. Nat Prod Rep. 2014;31:1348–75.

    Article  CAS  PubMed  Google Scholar 

  3. Süssmuth R, Müller J, von Döhren H, Molnár I. Fungal cyclooligomer depsipeptides: from classical biochemistry to combinatorial biosynthesis. Nat Prod Rep. 2011;28:99–124.

    Article  PubMed  Google Scholar 

  4. Felnagle EA, et al. Nonribosomal peptide synthetases involved in the production of medically relevant natural products. Mol Pharm. 2008;5:191–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Duclohier H. Peptaibiotics and peptaibols: an alternative to classical antibiotics? Chem Biodivers. 2007;4:1023–6.

    Article  CAS  PubMed  Google Scholar 

  6. Paterson Y, Rumsey SM, Benedetti E, Nemethy G, Scheraga HA. Sensitivity of polypeptide conformation to geometry. Theoretical conformational analysis of oligomers of α-aminoisobutyric acid. J Am Chem Soc. 1981;103:2947–55.

    Article  CAS  Google Scholar 

  7. Smith GD, et al. Crystal structures and conformational calculations of fragments of alamethicin containing aminoisobutyric acid. J Am Chem Soc. 1981;103:1493–501.

    Article  CAS  Google Scholar 

  8. Benedetti E, et al. Peptaibol antibiotics: a study on the helical structure of the 2–9 sequence of emerimicins III and IV. Proc Natl Acad Sci USA. 1982;79:7951–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Marshall GR, et al. Factors governing helical preference of peptides containing multiple α,α-dialkyl amino acids. Proc Natl Acad Sci USA. 1990;87:487–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fox RO, Richards FM. A voltage-gated ion channel model inferred from the crystal structure of alamethicin at 1.5-Å resolution. Nature. 1982;300:325–30.

    Article  CAS  PubMed  Google Scholar 

  11. Pieta P, Mirza J, Lipkowski J. Direct visualization of the alamethicin pore formed in a planar phospholipid matrix. Proc Natl Acad Sci USA. 2012;109:21223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang C, et al. Acremotins A–D, peptaibiotics produced by the soil-derived fungus Acremonium persicinum SC0105. J Antibiot. 2018;71:927–38.

    Article  CAS  Google Scholar 

  13. van Bohemen AI, et al. Pentadecaibins I–V: 15-residue peptaibols produced by a marine-derived Trichoderma sp. of the Harzianum clade. J Nat Prod. 2021;84:1271–82.

    Article  PubMed  Google Scholar 

  14. Lee JW, Collins JE, Wendt KL, Chakrabarti D, Cichewicz RH. Leveraging peptaibol biosynthetic promiscuity for next-generation antiplasmodial therapeutics. J Nat Prod. 2021;84:503–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rawa MSA, et al. Zealpeptaibolin, an 11-mer cytotoxic peptaibol group with 3 Aib-Pro motifs isolated from Trichoderma sp. RK10-F026. J Antibiot. 2021;74:485–95.

    Article  CAS  Google Scholar 

  16. Singh VP, et al. Lipovelutibols A–D: cytotoxic lipopeptaibols from the Himalayan cold habitat fungus Trichoderma velutinum. J Nat Prod. 2018;81:219–26.

    Article  CAS  PubMed  Google Scholar 

  17. Flissi A, et al. Norine: update of the nonribosomal peptide resource. Nucleic Acids Res. 2020;48:D465–9.

    CAS  PubMed  Google Scholar 

  18. van Santen JA, et al. The Natural Products Atlas: an open access knowledge base for microbial natural products discovery. ACS Cent Sci. 2019;5:1824–33.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Harada K, et al. A method using LC/MS for determination of absolute configuration of constituent amino acids in peptide—advanced marfey’s method. Tetrahedron Lett. 1995;36:1515–8.

    Article  CAS  Google Scholar 

  20. Rowley DC, Kelly S, Kauffman CA, Jensen PR, Fenical W. Halovirs A–E, new antiviral agents from a marine-derived fungus of the genus Scytalidium. Bioorg Med Chem. 2003;11:4263–74.

    Article  CAS  PubMed  Google Scholar 

  21. Fenical W, Jensen PR, Rowley DC. Halovir, an antiviral marine natural product, and derivatives thereof. US20030013659A1 (2003).

  22. Whitmore L, Wallace BA. The Peptaibol Database: a database for sequences and structures of naturally occurring peptaibols. Nucleic Acids Res. 2004;32:D593–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ritzau M, et al. Ampullosporin, a new peptaibol-type antibiotic from Sepedonium ampullosporum HKI-0053 with neuroleptic activity in mice. J Antibiot. 1997;50:722–8.

    Article  CAS  Google Scholar 

  24. Kronen M, Kleinwächter P, Schlegel B, Härtl A, Gräfe U, Ampullosporines B. C, D, E1, E2, E3 and E4 from Sepedonium ampullosporum HKI-0053: structures and biological activities. J Antibiot. 2001;54:175–8.

    Article  CAS  Google Scholar 

  25. Becker D, Kiess M, Brückner H. Structures of peptaibol antibiotics hypomurocin A and B from the ascomycetous fungus Hypocrea muroiana hino et katsumoto. Liebigs Ann. 1997;4:767–72.

    Article  Google Scholar 

  26. Bean GA, Fernando T, Jarvis BB, Bruton B. The isolation and identification of trichothecene metabolites from a plant pathogenic strain of Myrothecium roridum. J Nat Prod. 1984;47:727–9.

    Article  CAS  PubMed  Google Scholar 

  27. Jarvis BB, Yatawara CS. New macrocyclic trichothecenes from Myrothecium roridum. J Org Chem. 1986;51:2906–10.

    Article  CAS  Google Scholar 

  28. Abbas HK, et al. Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria. Phytochemistry. 2002;59:309–13.

    Article  CAS  PubMed  Google Scholar 

  29. Shen L, et al. Cytotoxic trichothecene macrolides produced by the endophytic Myrothecium roridum. J Nat Prod. 2019;82:1503–9.

    Article  CAS  PubMed  Google Scholar 

  30. Liu H, et al. Trichothecene macrolides from the endophytic fungus Paramyrothecium roridum and their cytotoxic activity. Fitoterapia. 2020;147:104768.

    Article  CAS  PubMed  Google Scholar 

  31. Zou X, et al. Verrucamides A–D, antibacterial cyclopeptides from Myrothecium verrucaria. J Nat Prod. 2011;74:1111–6.

    Article  CAS  PubMed  Google Scholar 

  32. Yoshimura A, et al. Isolation, structure elucidation, and conformational regulation of myropeptins, lipopeptides from the fungus Myrothecium roridum. Org Lett. 2019;21:7524–8.

    Article  CAS  PubMed  Google Scholar 

  33. Blin K, et al. AntiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 2019;47:W81–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cacho RA, Jiang W, Chooi YH, Walsh CT, Tang Y. Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440. J Am Chem Soc. 2012;134:16781–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen L, et al. Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis. BMC Genomics. 2013;14:339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wiest A, et al. Identification of peptaibols from Trichoderma virens and cloning of a peptaibol synthetase. J Biol Chem. 2002;277:20862–8.

    Article  CAS  PubMed  Google Scholar 

  37. Manavalan B, Murugapiran SK, Lee G, Choi S. Molecular modeling of the reductase domain to elucidate the reaction mechanism of reduction of peptidyl thioester into its corresponding alcohol in non-ribosomal peptide synthetases. BMC Struct Biol. 2010;10:1.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Magarvey NA, Haltli B, He M, Greenstein M, Hucul JA. Biosynthetic pathway for mannopeptimycins, lipoglycopeptide antibiotics active against drug-resistant gram-positive pathogens. Antimicrob Agents Chemother. 2006;50:2167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thomas MG, Chan YA, Ozanick SG. Deciphering tuberactinomycin biosynthesis: isolation, sequencing, and annotation of the viomycin biosynthetic gene cluster. Antimicrob Agents Chemother. 2003;47:2823–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Felnagle EA, Rondon MR, Berti AD, Crosby HA, Thomas MG. Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin. Appl Environ Microbiol. 2007;73:4162–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang JJ, Tang X, Huan T, Ross AC, Moore BS. Pass-back chain extension expands multimodular assembly line biosynthesis. Nat Chem Biol. 2020;16:42–9.

    Article  CAS  PubMed  Google Scholar 

  42. Röttig M, et al. NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res. 2011;39:W362–7.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Onishi HR, et al. Antibacterial agents that inhibit lipid A biosynthesis. Science. 1996;274:980.

    Article  CAS  PubMed  Google Scholar 

  44. Shi J-F, Wu P, Jiang Z-H, Wei X-Y. Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins. Eur J Med Chem. 2014;71:219–28.

    Article  CAS  PubMed  Google Scholar 

  45. Wang C, Wu P, Shi J-F, Jiang Z-H, Wei X-Y. Synthesis and cancer cell growth inhibitory activity of icaritin derivatives. Eur J Med Chem. 2015;100:139–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (32170070 to CW, and 32070053 and 31870076 to YX); the Central Public-interest Scientific Institution Basal Research Fund (No. 1610392021004 to CW); the Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences (CAAS-ASTIP to YX). The authors acknowledge Dr Lida Han (Research Facility Center of Biotechnology Research Institute) for the HRESIMS measurements.

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Authors and Affiliations

  1. Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, People’s Republic of China

    Dongliang Xiao, Tianyi Li, Wenhua Li, Liwen Zhang, Qun Yue, Yuquan Xu & Chen Wang

  2. Institute of Analysis and Testing, Beijing Academy of Science and Technology (Beijing Center for Physical and Chemical Analysis), 7 Fengxian Central Road, Beijing, 100094, People’s Republic of China

    Mei Zhang & Xinqi Chen

  3. Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, 723 Xingke Road, Guangzhou, 510650, People’s Republic of China

    Ping Wu & Xiaoyi Wei

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Xiao, D., Zhang, M., Wu, P. et al. Halovirs I–K, antibacterial and cytotoxic lipopeptaibols from the plant pathogenic fungus Paramyrothecium roridum NRRL 2183. J Antibiot 75, 247–257 (2022). https://doi.org/10.1038/s41429-022-00517-7

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