In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.
The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filari...
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| _version_ | 1850205856991281152 |
|---|---|
| author | Alexandra Ehrens Christopher S Lunde Robert T Jacobs Dominique Struever Marianne Koschel Stefan J Frohberger Franziska Lenz Martina Fendler Joseph D Turner Stephen A Ward Mark J Taylor Yvonne R Freund Rianna Stefanakis Eric Easom Xianfeng Li Jacob J Plattner Achim Hoerauf Marc P Hübner |
| author_facet | Alexandra Ehrens Christopher S Lunde Robert T Jacobs Dominique Struever Marianne Koschel Stefan J Frohberger Franziska Lenz Martina Fendler Joseph D Turner Stephen A Ward Mark J Taylor Yvonne R Freund Rianna Stefanakis Eric Easom Xianfeng Li Jacob J Plattner Achim Hoerauf Marc P Hübner |
| author_sort | Alexandra Ehrens |
| collection | DOAJ |
| description | The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis. |
| format | Article |
| id | doaj-art-dec6d4c0192a4b7f912f2690a17c0fac |
| institution | OA Journals |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-dec6d4c0192a4b7f912f2690a17c0fac2025-08-20T02:11:00ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352020-01-01141e000795710.1371/journal.pntd.0007957In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.Alexandra EhrensChristopher S LundeRobert T JacobsDominique StrueverMarianne KoschelStefan J FrohbergerFranziska LenzMartina FendlerJoseph D TurnerStephen A WardMark J TaylorYvonne R FreundRianna StefanakisEric EasomXianfeng LiJacob J PlattnerAchim HoeraufMarc P HübnerThe elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.https://storage.googleapis.com/plos-corpus-prod/10.1371/journal.pntd.0007957/2/pntd.0007957.pdf?X-Goog-Algorithm=GOOG4-RSA-SHA256&X-Goog-Credential=wombat-sa%40plos-prod.iam.gserviceaccount.com%2F20210222%2Fauto%2Fstorage%2Fgoog4_request&X-Goog-Date=20210222T071714Z&X-Goog-Expires=3600&X-Goog-SignedHeaders=host&X-Goog-Signature=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 |
| spellingShingle | Alexandra Ehrens Christopher S Lunde Robert T Jacobs Dominique Struever Marianne Koschel Stefan J Frohberger Franziska Lenz Martina Fendler Joseph D Turner Stephen A Ward Mark J Taylor Yvonne R Freund Rianna Stefanakis Eric Easom Xianfeng Li Jacob J Plattner Achim Hoerauf Marc P Hübner In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. PLoS Neglected Tropical Diseases |
| title | In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. |
| title_full | In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. |
| title_fullStr | In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. |
| title_full_unstemmed | In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. |
| title_short | In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. |
| title_sort | in vivo efficacy of the boron pleuromutilin an11251 against wolbachia of the rodent filarial nematode litomosoides sigmodontis |
| url | https://storage.googleapis.com/plos-corpus-prod/10.1371/journal.pntd.0007957/2/pntd.0007957.pdf?X-Goog-Algorithm=GOOG4-RSA-SHA256&X-Goog-Credential=wombat-sa%40plos-prod.iam.gserviceaccount.com%2F20210222%2Fauto%2Fstorage%2Fgoog4_request&X-Goog-Date=20210222T071714Z&X-Goog-Expires=3600&X-Goog-SignedHeaders=host&X-Goog-Signature=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 |
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