gms | German Medical Science

Infektiologie Update 2018: 26. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

04. - 06.10.2018, Wien, Österreich

Insects in anthelmintics discovery: lady beetle-derived harmonine as novel anti-parasitic “swiss army-knife”?

Meeting Abstract

  • S. Haeberlein - Institute of Parasitology, BFS, Justus-Liebig-University Gießen
  • J. Kellershohn - Institute of Parasitology, BFS, Justus-Liebig-University Gießen
  • L. Thomas - Institute of Pharmaceutical Chemistry, Philipps University Marburg
  • B. Spengler - Institute of Inorganic and Analytical Chemistry, Justus-Liebig-University Gießen
  • A. Grünweller - Institute of Pharmaceutical Chemistry, Philipps University Marburg
  • A. Vilcinskas - Institute for Insect Biotechnology, Justus-Liebig-University Gießen; Department Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Gießen
  • C. G. Grevelding - Institute of Parasitology, BFS, Justus-Liebig-University Gießen

Infektiologie Update 2018. 26. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG). Wien, 04.-06.10.2018. Düsseldorf: German Medical Science GMS Publishing House; 2018. Doc18peg29

doi: 10.3205/18peg29, urn:nbn:de:0183-18peg293

Veröffentlicht: 8. Oktober 2018

© 2018 Haeberlein et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Insects represent an innovative source for the discovery of novel anti-parasitic compounds. Harmonine is an antimicrobial compound of the invasive Asian lady beetle Harmonia axyridis [1]. Pilot studies have shown that harmonine has a remarkable all-round activity against mycobacteria and protozoans such as Plasmodium and Leishmania parasites [2], [3]. To explore the anthelminthic potential of harmonine against platyhelminths, we tested its effect on the blood fluke Schistosoma mansoni and the common liver fluke Fasciola hepatica; both have zoonotic potential and affect millions of people and livestock worldwide. For both flukes, identification of novel drugs is pressing because of the unavailability of vaccines, and because of upcoming or already existing resistances against the current drugs in use.

In vitro studies showed that harmonine was lethal to adult S. mansoni at concentrations as low as 10 µM. With 5 µM, the motility was reduced to a minimum, female and male worms separated, and egg production was fully abolished. Tegument blisters and prominent gut dilatations were observed. Confocal laser scanning microscopy revealed structural disintegration of the male and female reproductive organs, including reduced sperm numbers and a significant reduction of proliferating gonadal stem cells. These findings point to a cellular target of harmonine involved in gonad development or function. In an independent in-silico modeling study, acetylcholinesterase (AChE) was predicted as one possible target. Indeed, harmonine partially inhibited the acetylcholine-hydrolyzing activity of recombinant AChE activity and schistosomal protein extracts. Comparative RNA-seq [4] as well as qPCR analyses revealed an interesting pairing-dependent expression difference of an AChE orthologue in female S. mansoni. Besides schistosomes, juvenile F. hepatica were killed by harmonine in vitro, here in concentrations as low as 2.5 µM.

To conclude, in addition to its antimicrobial and antiprotozoal effects, harmonine demonstrated also anthelminthic activity. Besides promoting this insect-derived compound as an attractive candidate for further development, this pilot study in general encourages to explore insect-derived molecules for novel antiparasitics.


References

1.
Vilcinskas A, Stoecker K, Schmidtberg H, Röhrich CR, Vogel H. Invasive harlequin ladybird carries biological weapons against native competitors. Science. 2012;340:862-3.
2.
Nagel NC, Masic A, Schurigt U, Boland W. Efficient synthesis of (R)-harmonine - the toxic principle of the multicolored Asian lady beetle (Harmonia axyridis). Org Biomol Chem. 2005;13:5139-46.
3.
Röhrich C, Ngwa CJ, Wiesner J, Schmidtberg H, Degenkolb T, Kollewe C, Fischer R, Pradel G, Vilcinskas A. Harmonine, a defence compound from the harlequin ladybird, inhibits mycobacterial growth and demonstrates multi-stage antimalarial activity. Biol Lett. 2012;8:308-11.
4.
Lu Z, Sessler F, Holroyd N, Hahnel S, Quack T, Berriman M, Grevelding CG. Schistosome sex matters: a deep view into gonad-specific and pairing-dependent transcriptomes reveals a complex gender interplay. Sci Rep. 2016;6:31150.