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Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro.
ACS Chem Neurosci. 2020 May 26 [Online ahead of print]AC

Abstract

Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, Naegleria fowleri, leads to extensive inflammation of the brain and death within 3-7 days after symptoms begin. Treatment of primary amebic meningoencephalitis relies on amphotericin B in combination with other drugs, but use of amphotericin B is associated with severe adverse effects. Despite a fatality rate of over 97%, economic incentive to invest in development of antiamebic drugs by the pharmaceutical industry is lacking. Development of safe and rapidly acting drugs remains a critical unmet need to avert future deaths. Since FDA-approved anti-inflammatory and antiarthritic drug auranofin is a known inhibitor of selenoprotein synthesis and thioredoxin reductase and the genome of N. fowleri encodes genes for both selenocysteine biosynthesis and thioredoxin reductases, we tested the effect of auranofin against N. fowleri strains of different genotypes from the USA, Europe, and Australia. Auranofin was equipotent against all tested strains with an EC50 of 1-2 μM. Our growth inhibition study at different time points demonstrated that auranofin is fast-acting, and ∼90% growth inhibition was achieved within 16 h of drug exposure. A short exposure of N. fowleri to auranofin led to the accumulation of intracellular reactive oxygen species. This is consistent with auranofin's role in inhibiting antioxidant pathways. Further, combination of auranofin and amphotericin B led to 95% of growth inhibition with 2-9-fold dose reduction for amphotericin B and 3-20-fold dose reduction for auranofin. Auranofin has the potential to be repurposed for the treatment of primary amebic meningoencephalitis.

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, California 92093-0756, United States.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0756, United States.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0756, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32392039

Citation

Escrig, Jose Ignacio, et al. "Activity of Auranofin Against Multiple Genotypes of Naegleria Fowleri and Its Synergistic Effect With Amphotericin B in Vitro." ACS Chemical Neuroscience, 2020.
Escrig JI, Hahn HJ, Debnath A. Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro. ACS Chem Neurosci. 2020.
Escrig, J. I., Hahn, H. J., & Debnath, A. (2020). Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.0c00165
Escrig JI, Hahn HJ, Debnath A. Activity of Auranofin Against Multiple Genotypes of Naegleria Fowleri and Its Synergistic Effect With Amphotericin B in Vitro. ACS Chem Neurosci. 2020 May 26; PubMed PMID: 32392039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro. AU - Escrig,Jose Ignacio, AU - Hahn,Hye Jee, AU - Debnath,Anjan, Y1 - 2020/05/26/ PY - 2020/5/12/pubmed PY - 2020/5/12/medline PY - 2020/5/12/entrez KW - Naegleria KW - amphotericin B KW - auranofin KW - drug KW - free-living ameba KW - primary amebic meningoencephalitis JF - ACS chemical neuroscience JO - ACS Chem Neurosci N2 - Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, Naegleria fowleri, leads to extensive inflammation of the brain and death within 3-7 days after symptoms begin. Treatment of primary amebic meningoencephalitis relies on amphotericin B in combination with other drugs, but use of amphotericin B is associated with severe adverse effects. Despite a fatality rate of over 97%, economic incentive to invest in development of antiamebic drugs by the pharmaceutical industry is lacking. Development of safe and rapidly acting drugs remains a critical unmet need to avert future deaths. Since FDA-approved anti-inflammatory and antiarthritic drug auranofin is a known inhibitor of selenoprotein synthesis and thioredoxin reductase and the genome of N. fowleri encodes genes for both selenocysteine biosynthesis and thioredoxin reductases, we tested the effect of auranofin against N. fowleri strains of different genotypes from the USA, Europe, and Australia. Auranofin was equipotent against all tested strains with an EC50 of 1-2 μM. Our growth inhibition study at different time points demonstrated that auranofin is fast-acting, and ∼90% growth inhibition was achieved within 16 h of drug exposure. A short exposure of N. fowleri to auranofin led to the accumulation of intracellular reactive oxygen species. This is consistent with auranofin's role in inhibiting antioxidant pathways. Further, combination of auranofin and amphotericin B led to 95% of growth inhibition with 2-9-fold dose reduction for amphotericin B and 3-20-fold dose reduction for auranofin. Auranofin has the potential to be repurposed for the treatment of primary amebic meningoencephalitis. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/32392039/Activity_of_Auranofin_against_Multiple_Genotypes_of_Naegleria_fowleri_and_Its_Synergistic_Effect_with_Amphotericin_B_In_Vitro L2 - https://doi.org/10.1021/acschemneuro.0c00165 DB - PRIME DP - Unbound Medicine ER -
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