Combinations of the azaquinazoline anti-<i>Wolbachia</i> agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis.


Hegde, Shrilakshmi, Marriott, Amy E ORCID: 0000-0002-4806-9539, Pionnier, Nicolas ORCID: 0000-0002-2379-4945, Steven, Andrew, Bulman, Christina, Gunderson, Emma, Vogel, Ian, Koschel, Marianne, Ehrens, Alexandra, Lustigman, Sara et al (show 13 more authors) (2024) Combinations of the azaquinazoline anti-<i>Wolbachia</i> agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis. Frontiers in microbiology, 15. 1346068-.

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Abstract

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-<i>Wolbachia</i> azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: <i>Brugia malayi-</i>CB.17 SCID mice<i>, B. malayi-</i>Mongolian gerbils, <i>B. pahangi-</i>Mongolian gerbils, and <i>Litomosoides sigmodontis-</i>Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) <i>Wolbachia</i> 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 <i>B. pahangi</i> and <i>L. sigmodontis</i> gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of <i>Wolbachia</i> populations within both germline and hypodermal tissues of <i>B. malayi</i> female worms and in hypodermal tissues in male worms, indicating that anti-<i>Wolbachia</i> 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-<i>Wolbachia</i> agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.

Item Type: Article
Uncontrolled Keywords: AWZ1066S, Wolbachia, anti-Wolbachia drugs, benzimidazole, lymphatic filariasis, macrofilaricidal drugs, onchocerciasis
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 07 Mar 2024 15:48
Last Modified: 07 Mar 2024 15:49
DOI: 10.3389/fmicb.2024.1346068
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3179222
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