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In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri.
Front Microbiol. 2018; 9:414.FM

Abstract

Primary amebic meningoencephalitis (PAM) is a fatal infection caused by the free-living ameba Naegleria fowleri, popularly known as the "brain-eating ameba." The drugs of choice in treating PAM are the antifungal amphotericin B and an antileishmanial miltefosine, but these are not FDA-approved for this indication and use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with the combination therapy have survived PAM. Therefore, development of efficient drugs is a critical unmet need to avert future deaths of children. Since N. fowleri causes extensive inflammation in the brain it is important to select compounds that can enter brain to kill ameba. In this study, we identified two central nervous system (CNS) active compounds, ebselen and BAY 11-7082 as amebicidal with EC50 of 6.2 and 1.6 μM, respectively. The closely related BAY 11-7085 was also found active against N. fowleri with EC50 similar to BAY 11-7082. We synthesized a soluble ebselen analog, which had amebicidal activity similar to ebselen. Transmission electron microscopy of N. fowleri trophozoites incubated for 48 h with EC50 concentration of ebselen showed alteration in the cytoplasmic membrane, loss of the nuclear membrane, and appearance of electron-dense granules. Incubation of N. fowleri trophozoites with EC50 concentrations of BAY 11-7082 and BAY 11-7085 for 48 h showed the presence of large lipid droplets in the cytoplasm, disruption of cytoplasmic and nuclear membranes and appearance of several vesicles and chromatin residues. Blood-brain barrier permeable amebicidal compounds have potential as new drug leads for Naegleria infection.

Authors+Show Affiliations

Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.Department of Infectomics and Molecular Pathogenesis, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.Department of Infectomics and Molecular Pathogenesis, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29559968

Citation

Debnath, Anjan, et al. "In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria Fowleri." Frontiers in Microbiology, vol. 9, 2018, p. 414.
Debnath A, Nelson AT, Silva-Olivares A, et al. In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri. Front Microbiol. 2018;9:414.
Debnath, A., Nelson, A. T., Silva-Olivares, A., Shibayama, M., Siegel, D., & McKerrow, J. H. (2018). In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri. Frontiers in Microbiology, 9, 414. https://doi.org/10.3389/fmicb.2018.00414
Debnath A, et al. In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria Fowleri. Front Microbiol. 2018;9:414. PubMed PMID: 29559968.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri. AU - Debnath,Anjan, AU - Nelson,Andrew T, AU - Silva-Olivares,Angélica, AU - Shibayama,Mineko, AU - Siegel,Dionicio, AU - McKerrow,James H, Y1 - 2018/03/06/ PY - 2017/11/27/received PY - 2018/02/21/accepted PY - 2018/3/22/entrez PY - 2018/3/22/pubmed PY - 2018/3/22/medline KW - BAY 11-7082 KW - BAY 11-7085 KW - Naegleria KW - chemotherapy KW - drug KW - ebselen KW - free-living ameba KW - parasite SP - 414 EP - 414 JF - Frontiers in microbiology JO - Front Microbiol VL - 9 N2 - Primary amebic meningoencephalitis (PAM) is a fatal infection caused by the free-living ameba Naegleria fowleri, popularly known as the "brain-eating ameba." The drugs of choice in treating PAM are the antifungal amphotericin B and an antileishmanial miltefosine, but these are not FDA-approved for this indication and use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with the combination therapy have survived PAM. Therefore, development of efficient drugs is a critical unmet need to avert future deaths of children. Since N. fowleri causes extensive inflammation in the brain it is important to select compounds that can enter brain to kill ameba. In this study, we identified two central nervous system (CNS) active compounds, ebselen and BAY 11-7082 as amebicidal with EC50 of 6.2 and 1.6 μM, respectively. The closely related BAY 11-7085 was also found active against N. fowleri with EC50 similar to BAY 11-7082. We synthesized a soluble ebselen analog, which had amebicidal activity similar to ebselen. Transmission electron microscopy of N. fowleri trophozoites incubated for 48 h with EC50 concentration of ebselen showed alteration in the cytoplasmic membrane, loss of the nuclear membrane, and appearance of electron-dense granules. Incubation of N. fowleri trophozoites with EC50 concentrations of BAY 11-7082 and BAY 11-7085 for 48 h showed the presence of large lipid droplets in the cytoplasm, disruption of cytoplasmic and nuclear membranes and appearance of several vesicles and chromatin residues. Blood-brain barrier permeable amebicidal compounds have potential as new drug leads for Naegleria infection. SN - 1664-302X UR - https://www.unboundmedicine.com/medline/citation/29559968/In_Vitro_Efficacy_of_Ebselen_and_BAY_11_7082_Against_Naegleria_fowleri_ L2 - https://doi.org/10.3389/fmicb.2018.00414 DB - PRIME DP - Unbound Medicine ER -
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