Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease

Nixon, Gemma L., McEntee, Laura, Johnson, Adam, Farrington, Nicola, Whalley, Sarah, Livermore, Joanne, Natal, Cristien, Washbourn, Gina, Bibby, Jaclyn, Berry, Neil, Lestner, Jodi, Truong, Megan, Owen, Andrew, Lalloo, David, Charles, Ian and Hope, William (2018) Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease. Antimicrobial Agents and Chemotherapy, 62 (4). e01909-17. ISSN 0066-4804

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Abstract

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

Item Type: Article
Uncontrolled Keywords: cryptococcus neoformans,cryptococcal meningoencephalitis,benzimidazole flubendazole,β-tubulin,antifungal agents,cryptococcal,meningitis,pharmacodynamics,pharmacokinetics,tubulin
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: Pure Connector
Date Deposited: 05 Apr 2018 11:30
Last Modified: 22 Jul 2020 02:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/66679
DOI: 10.1128/AAC.01909-17

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