Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>

ABSTRACT Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst f...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Matthew T. Laurie, Corin V. White, Hanna Retallack, Wesley Wu, Matthew S. Moser, Judy A. Sakanari, Kenny Ang, Christopher Wilson, Michelle R. Arkin, Joseph L. DeRisi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	amoeba antiparasitic agents balamuthia encephalitis nitroxoline Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dc0b924a0e4e4116b009021d93f76abd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:dc0b924a0e4e4116b009021d93f76abd
record_format	dspace
spelling	oai:doaj.org-article:dc0b924a0e4e4116b009021d93f76abd2021-11-15T15:58:20ZFunctional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>10.1128/mBio.02051-182150-7511https://doaj.org/article/dc0b924a0e4e4116b009021d93f76abd2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02051-18https://doaj.org/toc/2150-7511ABSTRACT Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections. IMPORTANCE Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections.Matthew T. LaurieCorin V. WhiteHanna RetallackWesley WuMatthew S. MoserJudy A. SakanariKenny AngChristopher WilsonMichelle R. ArkinJoseph L. DeRisiAmerican Society for Microbiologyarticleamoebaantiparasitic agentsbalamuthiaencephalitisnitroxolineMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	amoeba antiparasitic agents balamuthia encephalitis nitroxoline Microbiology QR1-502
spellingShingle	amoeba antiparasitic agents balamuthia encephalitis nitroxoline Microbiology QR1-502 Matthew T. Laurie Corin V. White Hanna Retallack Wesley Wu Matthew S. Moser Judy A. Sakanari Kenny Ang Christopher Wilson Michelle R. Arkin Joseph L. DeRisi Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
description	ABSTRACT Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections. IMPORTANCE Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections.
format	article
author	Matthew T. Laurie Corin V. White Hanna Retallack Wesley Wu Matthew S. Moser Judy A. Sakanari Kenny Ang Christopher Wilson Michelle R. Arkin Joseph L. DeRisi
author_facet	Matthew T. Laurie Corin V. White Hanna Retallack Wesley Wu Matthew S. Moser Judy A. Sakanari Kenny Ang Christopher Wilson Michelle R. Arkin Joseph L. DeRisi
author_sort	Matthew T. Laurie
title	Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
title_short	Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
title_full	Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
title_fullStr	Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
title_full_unstemmed	Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>
title_sort	functional assessment of 2,177 u.s. and international drugs identifies the quinoline nitroxoline as a potent amoebicidal agent against the pathogen <italic toggle="yes">balamuthia mandrillaris</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/dc0b924a0e4e4116b009021d93f76abd
work_keys_str_mv	AT matthewtlaurie functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT corinvwhite functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT hannaretallack functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT wesleywu functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT matthewsmoser functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT judyasakanari functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT kennyang functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT christopherwilson functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT michellerarkin functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic AT josephlderisi functionalassessmentof2177usandinternationaldrugsidentifiesthequinolinenitroxolineasapotentamoebicidalagentagainstthepathogenitalictoggleyesbalamuthiamandrillarisitalic
_version_	1718427059305316352

Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen <italic toggle="yes">Balamuthia mandrillaris</italic>

Ejemplares similares