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

Nixon, Gemma L, McEntee, Laura, Johnson, Adam ORCID: 0000-0002-6684-3321, Farrington, Nikki, Whalley, Sarah, Livermore, Joanne, Natal, Cristien, Washbourn, Gina, Bibby, Jaclyn, Berry, Neil ORCID: 0000-0003-1928-0738
et al (show 6 more authors) (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-e01917.

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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 anti-parasitic 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/L using European Committee for Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal ß-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/day) orally resulted in a ∼2 log10CFU/g reduction in fungal burden compared with vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the 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, beta-tubulin, antifungal agents, cryptococcal, meningitis, pharmacodynamics, pharmacokinetics, tubulin
Depositing User: Symplectic Admin
Date Deposited: 15 Jan 2018 07:47
Last Modified: 19 Jan 2023 06:44
DOI: 10.1128/aac.01909-17
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