AUTHOR=Ferrins Lori , Buskes Melissa J. , Kapteyn Madison M. , Engels Hannah N. , Enos Suzanne E. , Lu Chenyang , Klug Dana M. , Singh Baljinder , Quotadamo Antonio , Bachovchin Kelly , Tear Westley F. , Spaulding Andrew E. , Forbes Katherine C. , Bag Seema , Rivers Mitch , LeBlanc Catherine , Burchfield Erin , Armand Jeremy R. , Diaz-Gonzalez Rosario , Ceballos-Perez Gloria , García-Hernández Raquel , Pérez-Moreno Guiomar , Bosch-Navarrete Cristina , Gómez-Liñán Claudia , Ruiz-Pérez Luis Miguel , Gamarro Francisco , González-Pacanowska Dolores , Navarro Miguel , Mensa-Wilmot Kojo , Pollastri Michael P. , Kyle Dennis E. , Rice Christopher A. 

TITLE=Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1149145

DOI=10.3389/fmicb.2023.1149145

ISSN=1664-302X

ABSTRACT=<p><italic>Acanthamoeba</italic> species, <italic>Naegleria fowleri</italic>, and <italic>Balamuthia mandrillaris</italic> are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (&gt;90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: <bold>2d</bold> (<italic>A. castellanii</italic> EC<sub>50</sub>: 0.92 ± 0.3 μM; and <italic>N. fowleri</italic> EC<sub>50</sub>: 0.43 ± 0.13 μM), <bold>1c</bold> and <bold>2b</bold> (<italic>N. fowleri</italic> EC<sub>50</sub>s: &lt;0.63 μM, and 0.3 ± 0.21 μM), and <bold>4b</bold> and <bold>7b</bold> (<italic>B. mandrillaris</italic> EC<sub>50</sub>s: 1.0 ± 0.12 μM, and 1.4 ± 0.17 μM, respectively). With several of these pharmacophores already possessing blood–brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases.</p>