The activities of wortmannilactones against helminth electron transport chain enzymes, structure-activity relationships, and the effect on Trichinella spiralis infected mice

Abstract

Biotransformation of wortmannilactone F (3) using the marine-derived fungus DL1103 generated wortmannilactone M (1), a novel analog of wortmannilactone, which was a reduction product of 3 at the C-3 carbonyl group. The in vitro inhibitory activities of 10 wortmannilactones, including 1, against electron transport enzymes indicated that all the wortmannilactones were selective inhibitors of NADH-fumarate reductase and NADH–rhodoquinone reductase. The structure–activity relationship analysis showed that the relative configuration of C1” and C5”, the positions of double bonds, the oxygen atoms in the dihydropyran moiety, and the keto-carbonyl group in the oxabicyclo-[2.2.1]-heptane moiety were important to the inhibitory activity of wortmannilactones. In vivo studies indicated that 3 significantly decreased the number and size of adult worms in Trichinella spiralis-infected mice in a dose-dependent manner. Notable changes in the cuticle and microvilli of T. spiralis were also observed. Our data provided useful information in the research and development of polyketides with dihydropyran and oxabicyclo [2.2.1] heptane moieties as antihelminthics.

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References

  1. 1.

    Hotez PJ, et al. Helminth infections: the great neglected tropical diseases. J Clin Invest. 2008;118:1311–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Otake H. Schistosomiasis: number of people treated worldwide in 2013. Wkly Epidemiol Rec. 2015;90:25–32.

    Google Scholar 

  3. 3.

    Anthony RM, Rutitzky LI, Urban JF Jr, Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nat Rev Immunol. 2007;7:975–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Robertson SJ, Martin RJ. Levamisole-activated single-channel currents from muscle of the nematode parasite Ascaris suum. Br J Pharmacol. 1993;108:170–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Dent JA, Smith MM, Vassilatis DK, Avery L. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc Natl Acad Sci USA. 2000;97:2674–9.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Arena JP. Expression of Caenorhabditis elegans mRNA in n Xenopus oocytes: a model system to study the mechanism of action of avermectins. Parasitol Today. 1994;10:35–37.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Lacey E, Gill JH. Biochemistry of benzimidazole resistance. Acta Trop. 1994;56:245–62.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Gardner DR, Brezden BL. The sites of action of praziquantel in a smooth muscle of Lymnaea stagnalis. Can J Physiol Pharmacol. 1984;62:282–7.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Lewis JA, Wu CH, Berg H, Levine JH. The genetics of ivermectin resistance in Caenorhabditis elegans. Genetics. 1980;95:905–28.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. 10.

    Towers PR, Edwards B, Richmond JE, Sattelle DB. The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor alpha subunit. J Neurochem. 2005;93:1–9.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Kita K, Takamiya S. Electron-transfer complexes in Ascaris mitochondria. Adv Parasitol. 2002;51:95–131.

    Article  PubMed  Google Scholar 

  12. 12.

    Mori M, et al. Ukulactones A and B, new NADH-fumarate reductase inhibitors produced by Penicillium sp. FKI-3389. Tetrahedron. 2011;67:6582–6.

    Article  CAS  Google Scholar 

  13. 13.

    Matsumoto J, et al. Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis. Antimicrob Agents Chemother. 2008;52:164–70.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Sakai C, Tomitsuka E, Esumi H, Harada S, Kita K. Mitochondrial fumarate reductase as a target of chemotherapy: From parasites to cancer cells. Biochim Biohpys Acta. 2012;1820:643–51.

    Article  CAS  Google Scholar 

  15. 15.

    Omura S, et al. An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria. Proc Natl Acad Sci USA. 2001;98:60–62.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Lang G, Wiese J, Schmaljohann R, Imhoff JF. New pentaenes from the sponge-derived marine fungus Penicillium rugulosum: structure determination and biosynthetic studies. Tetrahedron. 2007;63:11844–9.

    Article  CAS  Google Scholar 

  17. 17.

    Kaifuchi S, Mori M, Nonaka K, Masuma R, Ōmura S, Shiomi K. Ukulactone C, a new NADH-fumarate reductase inhibitor produced by Talaromyces sp. FKI-6713. J Gen Appl Microbiol. 2015;61:57–62.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Dong YS. et al. Cathepsin B inhibitory tetraene lactones from the fungus Talaromyces wortmannii. Helv Chim Acta. 2009;29:567–74.

    Article  Google Scholar 

  19. 19.

    Liu WC, et al. Wortmannilactones I–L, new NADH-fumarate reductase inhibitors, induced by adding suberoylanilide hydroxamic acid to the culture medium of Talaromyces wortmannii. Bioorg Med Chem Lett. 2016;26:5328–33.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Liu WC, et al. Production of polyketides with anthelmintic activity by the fungus Talaromyces wortmannii using one strain-many compounds (OSMAC) method. Phytochem Lett. 2016;18:157–61.

    Article  CAS  Google Scholar 

  21. 21.

    Tomitsuka E, Kita K, Esumi H. An anticancer agent, pyrvinium pamoate inhibits the NADH–fumarate reductase system-a unique mitochondrial energy metabolism in tumour microenvironments. J Biochem. 2012;152:171–83.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Ui H, et al. Nafuredin, a novel inhibitor of NADH-fumarate reductase, produced by Aspergillus niger FT-0554. J Antibiot. 2001;54:234–8.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Shiomi K, et al. Verticipyrone, a new NADH-fumarate reductase inhibitor, produced by Verticillium sp. FKI-1083. J Antibiot. 2006;59:785–90.

    Article  PubMed  Google Scholar 

  24. 24.

    Rodriguez-Caabeiro F, Criado-Fornelio A, Jimenez-Gonzalez A. A comparative study of the succinate dehydrogenase-fumarate reductase complex in the genus Trichinella. Parasitology. 1985;91(Pt):577.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Kita K, Hirawake H, Miyadera H, Amino H, Takeo S. Role of complex II in anaerobic respiration of the parasite mitochondria from Ascaris suum and Plasmodium falciparum. Biochim Biohpys Acta. 2002;1553:123–39.

    Article  CAS  Google Scholar 

  26. 26.

    Matadamas-Martínez F, et al. Analysis of the effect of a 2-(trifluoromethyl)-1 H -benzimidazole derivative on Trichinella spiralis muscle larvae. Vet Parasitol. 2013;194:193–7.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Moore HW, Folkers K. Coenzyme Q. LXII. Structure and synthesis of rhodoquinone, a natural aminoquinone of the coenzyme Q group 1. J Am Chem Soc. 1965;87:1409–10.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81172966). We are grateful to Dr. Jun Kun, Dalian University of Technology, for help in obtaining NMR and MS data and are grateful to Dr Yuanhua Qin, Department of Parasitology, College of Basic Medical Sciences, Dalian Medical University, for suggestions concerning the animal experiments.

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Correspondence to Yu Cui or Yue-Sheng Dong.

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Liu, WC., Ren, YX., Hao, AY. et al. The activities of wortmannilactones against helminth electron transport chain enzymes, structure-activity relationships, and the effect on Trichinella spiralis infected mice. J Antibiot 71, 731–740 (2018). https://doi.org/10.1038/s41429-018-0061-z

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