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

• Main Authors: Alexandra Ehrens (Author), Christopher S Lunde (Author), Robert T Jacobs (Author), Dominique Struever (Author), Marianne Koschel (Author), Stefan J Frohberger (Author), Franziska Lenz (Author), Martina Fendler (Author), Joseph D Turner (Author), Stephen A Ward (Author), Mark J Taylor (Author), Yvonne R Freund (Author), Rianna Stefanakis (Author), Eric Easom (Author), Xianfeng Li (Author), Jacob J Plattner (Author), Achim Hoerauf (Author), Marc P Hübner (Author)
• Format: Book
• Published: Public Library of Science (PLoS), 2020-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1935-2727; 1935-2735; 10.1371/journal.pntd.0007957
• Keywords: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270
• Source: PLoS Neglected Tropical Diseases, Vol 14, Iss 1, p e0007957 (2020)

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.