Frontiers in Microbiology (May 2023)
Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
- Lori Ferrins,
- Melissa J. Buskes,
- Madison M. Kapteyn,
- Hannah N. Engels,
- Suzanne E. Enos,
- Suzanne E. Enos,
- Chenyang Lu,
- Dana M. Klug,
- Baljinder Singh,
- Antonio Quotadamo,
- Antonio Quotadamo,
- Kelly Bachovchin,
- Westley F. Tear,
- Andrew E. Spaulding,
- Katherine C. Forbes,
- Seema Bag,
- Mitch Rivers,
- Catherine LeBlanc,
- Erin Burchfield,
- Jeremy R. Armand,
- Rosario Diaz-Gonzalez,
- Gloria Ceballos-Perez,
- Raquel García-Hernández,
- Guiomar Pérez-Moreno,
- Cristina Bosch-Navarrete,
- Claudia Gómez-Liñán,
- Luis Miguel Ruiz-Pérez,
- Francisco Gamarro,
- Dolores González-Pacanowska,
- Miguel Navarro,
- Kojo Mensa-Wilmot,
- Michael P. Pollastri,
- Dennis E. Kyle,
- Christopher A. Rice,
- Christopher A. Rice,
- Christopher A. Rice
Affiliations
- Lori Ferrins
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Melissa J. Buskes
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Madison M. Kapteyn
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Hannah N. Engels
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Suzanne E. Enos
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Suzanne E. Enos
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, United States
- Chenyang Lu
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- Dana M. Klug
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Baljinder Singh
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Antonio Quotadamo
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Antonio Quotadamo
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
- Kelly Bachovchin
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Westley F. Tear
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Andrew E. Spaulding
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Katherine C. Forbes
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Seema Bag
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Mitch Rivers
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Catherine LeBlanc
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Erin Burchfield
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Jeremy R. Armand
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Rosario Diaz-Gonzalez
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Gloria Ceballos-Perez
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Raquel García-Hernández
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Guiomar Pérez-Moreno
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Cristina Bosch-Navarrete
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Claudia Gómez-Liñán
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Luis Miguel Ruiz-Pérez
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Francisco Gamarro
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Dolores González-Pacanowska
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Miguel Navarro
- Instituto de Parasitología y Biomedicina “López-Neyra” Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain
- Kojo Mensa-Wilmot
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, United States
- Michael P. Pollastri
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States
- Dennis E. Kyle
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Christopher A. Rice
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Christopher A. Rice
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, United States
- Christopher A. Rice
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- DOI
- https://doi.org/10.3389/fmicb.2023.1149145
- Journal volume & issue
-
Vol. 14
Abstract
Acanthamoeba species, Naegleria fowleri, and Balamuthia mandrillaris 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 (>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: 2d (A. castellanii EC50: 0.92 ± 0.3 μM; and N. fowleri EC50: 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC50s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC50s: 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.
Keywords
- pathogenic free-living amoeba
- Acanthamoeba species
- Naegleria fowleri
- Balamuthia mandrillaris
- kinase inhibitors
- cross-screening
