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Open AccessArticle

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

by Christopher A. Rice 1,2,*,†,‡, Emma V. Troth 2,3,†, A. Cassiopeia Russell 2,3,† and Dennis E. Kyle 1,2,3,*
1
Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
2
Center for Tropical and Emerging Global Diseases, Athens, GA 30602, USA
3
Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA.
Pathogens 2020, 9(6), 476; https://doi.org/10.3390/pathogens9060476
Received: 12 May 2020 / Revised: 5 June 2020 / Accepted: 9 June 2020 / Published: 16 June 2020
Pathogenic free-living amoebae, Balamuthia mandrillaris, Naegleria fowleri, and several Acanthamoeba species are the etiological agents of severe brain diseases, with case mortality rates > 90%. A number of constraints including misdiagnosis and partially effective treatments lead to these high fatality rates. The unmet medical need is for rapidly acting, highly potent new drugs to reduce these alarming mortality rates. Herein, we report the discovery of new drugs as potential anti-amoebic agents. We used the CellTiter-Glo 2.0 high-throughput screening methods to screen the Medicines for Malaria Ventures (MMV) Pandemic Response Box in a search for new active chemical scaffolds. Initially, we screened the library as a single-point assay at 10 and 1 µM. From these data, we reconfirmed hits by conducting quantitative dose–response assays and identified 12 hits against B. mandrillaris, 29 against N. fowleri, and 14 against A. castellanii ranging from nanomolar to low micromolar potency. We further describe 11 novel molecules with activity against B. mandrillaris, 22 against N. fowleri, and 9 against A. castellanii. These structures serve as a starting point for medicinal chemistry studies and demonstrate the utility of phenotypic screening for drug discovery to treat diseases caused by free-living amoebae. View Full-Text
Keywords: MMV; Pandemic Response Box; phenotypic screening; drug discovery; Balamuthia mandrillaris; Naegleria fowleri; Acanthamoeba castellanii; antiparasitic agents MMV; Pandemic Response Box; phenotypic screening; drug discovery; Balamuthia mandrillaris; Naegleria fowleri; Acanthamoeba castellanii; antiparasitic agents
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Rice, C.A.; Troth, E.V.; Russell, A.C.; Kyle, D.E. Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii. Pathogens 2020, 9, 476.

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