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...
Published in: | PLOS Neglected Tropical Diseases |
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2020
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Online Access: | https://doi.org/10.1371/journal.pntd.0007957 https://doaj.org/article/dec6d4c0192a4b7f912f2690a17c0fac |
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ftdoajarticles:oai:doaj.org/article:dec6d4c0192a4b7f912f2690a17c0fac 2023-05-15T15:12:15+02:00 In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis. 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 2020-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007957 https://doaj.org/article/dec6d4c0192a4b7f912f2690a17c0fac EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007957 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007957 https://doaj.org/article/dec6d4c0192a4b7f912f2690a17c0fac PLoS Neglected Tropical Diseases, Vol 14, Iss 1, p e0007957 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007957 2022-12-31T02:25:13Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 1 e0007957 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 in Journal/Newspaper |
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 |
title |
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_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_sort |
in vivo efficacy of the boron-pleuromutilin an11251 against wolbachia of the rodent filarial nematode litomosoides sigmodontis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0007957 https://doaj.org/article/dec6d4c0192a4b7f912f2690a17c0fac |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 1, p e0007957 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007957 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007957 https://doaj.org/article/dec6d4c0192a4b7f912f2690a17c0fac |
op_doi |
https://doi.org/10.1371/journal.pntd.0007957 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
1 |
container_start_page |
e0007957 |
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1766342953319530496 |