AUTHOR=Hegde Shrilakshmi , Marriott Amy E. , Pionnier Nicolas , Steven Andrew , Bulman Christina , Gunderson Emma , Vogel Ian , Koschel Marianne , Ehrens Alexandra , Lustigman Sara , Voronin Denis , Tricoche Nancy , Hoerauf Achim , Hübner Marc P. , Sakanari Judy , Aljayyoussi Ghaith , Gusovsky Fabian , Dagley Jessica , Hong David W. , O'Neill Paul , Ward Steven A. , Taylor Mark J. , Turner Joseph D. 

TITLE=Combinations of the azaquinazoline anti-Wolbachia agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1346068

DOI=10.3389/fmicb.2024.1346068

ISSN=1664-302X

ABSTRACT=<p>Lymphatic filariasis and onchocerciasis are two major neglected tropical diseases that are responsible for causing severe disability in 50 million people worldwide, whilst veterinary filariasis (heartworm) is a potentially lethal parasitic infection of companion animals. There is an urgent need for safe, short-course curative (macrofilaricidal) drugs to eliminate these debilitating parasite infections. We investigated combination treatments of the novel anti-<italic>Wolbachia</italic> azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: <italic>Brugia malayi—</italic>CB.17 SCID mice<italic>, B. malayi—</italic>Mongolian gerbils, <italic>B. pahangi—</italic>Mongolian gerbils, and <italic>Litomosoides sigmodontis—</italic>Mongolian gerbils. Combination treatments synergised to elicit threshold (&gt;90%) <italic>Wolbachia</italic> depletion from female worms in 5 days of treatment, using 2-fold lower dose-exposures of AWZ1066S than monotherapy. Short-course lowered dose AWZ1066S-albendazole combination treatments also delivered partial adulticidal activities and/or long-lasting inhibition of embryogenesis, resulting in complete transmission blockade in <italic>B. pahangi</italic> and <italic>L. sigmodontis</italic> gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of <italic>Wolbachia</italic> populations within both germline and hypodermal tissues of <italic>B. malayi</italic> female worms and in hypodermal tissues in male worms, indicating that anti-<italic>Wolbachia</italic> synergy is not limited to targeting female embryonic tissues. Our data provides pre-clinical proof-of-concept that sub-seven-day combinations of rapid-acting novel anti-<italic>Wolbachia</italic> agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.</p>