期刊
PATHOGENS
卷 9, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/pathogens9060476
关键词
MMV; Pandemic Response Box; phenotypic screening; drug discovery; Balamuthia mandrillaris; Naegleria fowleri; Acanthamoeba castellanii; antiparasitic agents
类别
资金
- Georgia Research Alliance
Pathogenic free-living amoebae,Balamuthia mandrillaris,Naegleria fowleri, and severalAcanthamoebaspecies 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 mu M. From these data, we reconfirmed hits by conducting quantitative dose-response assays and identified 12 hits againstB. mandrillaris, 29 againstN. fowleri, and 14 againstA. castellaniiranging from nanomolar to low micromolar potency. We further describe 11 novel molecules with activity againstB. mandrillaris, 22 againstN. fowleri, and 9 againstA. 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.
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