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Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

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 whic...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206040/
https://www.ncbi.nlm.nih.gov/pubmed/37234530
http://dx.doi.org/10.3389/fmicb.2023.1149145
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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.
author_facet 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.
author_sort Ferrins, Lori
collection PubMed
description 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 EC(50): 0.92 ± 0.3 μM; and N. fowleri EC(50): 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC(50)s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC(50)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.
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spelling pubmed-102060402023-05-25 Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes 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. Front Microbiol Microbiology 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 EC(50): 0.92 ± 0.3 μM; and N. fowleri EC(50): 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC(50)s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC(50)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. Frontiers Media S.A. 2023-05-10 /pmc/articles/PMC10206040/ /pubmed/37234530 http://dx.doi.org/10.3389/fmicb.2023.1149145 Text en Copyright © 2023 Ferrins, Buskes, Kapteyn, Engels, Enos, Lu, Klug, Singh, Quotadamo, Bachovchin, Tear, Spaulding, Forbes, Bag, Rivers, LeBlanc, Burchfield, Armand, Diaz-Gonzalez, Ceballos-Perez, García-Hernández, Pérez-Moreno, Bosch-Navarrete, Gómez-Liñán, Ruiz-Pérez, Gamarro, González-Pacanowska, Navarro, Mensa-Wilmot, Pollastri, Kyle and Rice. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
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.
Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title_full Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title_fullStr Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title_full_unstemmed Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title_short Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
title_sort identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206040/
https://www.ncbi.nlm.nih.gov/pubmed/37234530
http://dx.doi.org/10.3389/fmicb.2023.1149145
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