In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.

Abstract

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.

• Authors: 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
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 14 Issue 1 Pg. e0007957 (01 2020) ISSN: 1935-2735 [Electronic] United States
• PMID: 31986143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Diterpenes
• Polycyclic Compounds
• pleuromutilin
• Doxycycline
• Boron
• Rifampin

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Boron
• Diterpenes (pharmacology)
• Doxycycline (pharmacology)
• Female
• Filariasis (drug therapy, microbiology)
• Filarioidea (drug effects, microbiology)
• Mice, Inbred BALB C
• Polycyclic Compounds (pharmacology)
• Rifampin (pharmacology)
• Symbiosis
• Wolbachia (drug effects)