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

Hegde, ShrilakshmI, Marriott, Amy, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, 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, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275 and Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476 (2024) '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'. Frontiers in Microbiology, Vol 15, p. 1346068. (In Press)

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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-Wolbachia azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: Brugia malayi—CB.17 SCID mice, B. malayi—Mongolian gerbils, B. pahangi—Mongolian gerbils, and Litomosoides sigmodontis—Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) Wolbachia 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 B. pahangi and L. sigmodontis gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of Wolbachia populations within both germline and hypodermal tissues of B. malayi female worms and in hypodermal tissues in male worms, indicating that anti-Wolbachia 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-Wolbachia 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
Subjects:	QW Microbiology and Immunology > Bacteria > QW 150 Proteobacteria. Rickettsiaceae, Wolbachia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.3389/fmicb.2024.1346068
Depositing User:	Clare O'Neill
Date Deposited:	06 Feb 2024 14:39
Last Modified:	19 Mar 2024 16:01
URI:	https://archive.lstmed.ac.uk/id/eprint/23961

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