Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis.

Abstract

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.

• Authors: Mark J Taylor, Thomas W von Geldern, Louise Ford, Marc P Hübner, Kennan Marsh, Kelly L Johnston, Hanna T Sjoberg, Sabine Specht, Nicolas Pionnier, Hayley E Tyrer, Rachel H Clare, Darren A N Cook, Emma Murphy, Andrew Steven, John Archer, Dominique Bloemker, Franziska Lenz, Marianne Koschel, Alexandra Ehrens, Haelly M Metuge, Valerinne C Chunda, Patrick W Ndongmo Chounna, Abdel J Njouendou, Fanny F Fombad, Robert Carr, Howard E Morton, Ghaith Aljayyoussi, Achim Hoerauf, Samuel Wanji, Dale J Kempf, Joseph D Turner, Stephen A Ward
• Journal: Science translational medicine (Sci Transl Med) Vol. 11 Issue 483 (03 13 2019) ISSN: 1946-6242 [Electronic] United States
• PMID: 30867321 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Chemical References

• Macrolides
• Tylosin

Topics

• Administration, Oral
• Animals
• Disease Models, Animal
• Elephantiasis, Filarial (blood, drug therapy, microbiology)
• Female
• Macrolides (administration & dosage, adverse effects, therapeutic use)
• Male
• Mice, Inbred BALB C
• Mice, SCID
• Onchocerciasis (blood, drug therapy, microbiology)
• Treatment Outcome
• Tylosin (blood, chemical synthesis, chemistry, therapeutic use)
• Wolbachia (physiology)