The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design

Abstract Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to com...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Isabelle Q. Phan, Christopher A. Rice, Justin Craig, Rooksana E. Noorai, Jacquelyn R. McDonald, Sandhya Subramanian, Logan Tillery, Lynn K. Barrett, Vijay Shankar, James C. Morris, Wesley C. Van Voorhis, Dennis E. Kyle, Peter J. Myler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f6501344d864a2aaccaf8376c641a80
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2f6501344d864a2aaccaf8376c641a80
record_format	dspace
spelling	oai:doaj.org-article:2f6501344d864a2aaccaf8376c641a802021-11-08T10:46:39ZThe transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design10.1038/s41598-021-99903-82045-2322https://doaj.org/article/2f6501344d864a2aaccaf8376c641a802021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99903-8https://doaj.org/toc/2045-2322Abstract Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.Isabelle Q. PhanChristopher A. RiceJustin CraigRooksana E. NooraiJacquelyn R. McDonaldSandhya SubramanianLogan TilleryLynn K. BarrettVijay ShankarJames C. MorrisWesley C. Van VoorhisDennis E. KylePeter J. MylerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Isabelle Q. Phan Christopher A. Rice Justin Craig Rooksana E. Noorai Jacquelyn R. McDonald Sandhya Subramanian Logan Tillery Lynn K. Barrett Vijay Shankar James C. Morris Wesley C. Van Voorhis Dennis E. Kyle Peter J. Myler The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
description	Abstract Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.
format	article
author	Isabelle Q. Phan Christopher A. Rice Justin Craig Rooksana E. Noorai Jacquelyn R. McDonald Sandhya Subramanian Logan Tillery Lynn K. Barrett Vijay Shankar James C. Morris Wesley C. Van Voorhis Dennis E. Kyle Peter J. Myler
author_facet	Isabelle Q. Phan Christopher A. Rice Justin Craig Rooksana E. Noorai Jacquelyn R. McDonald Sandhya Subramanian Logan Tillery Lynn K. Barrett Vijay Shankar James C. Morris Wesley C. Van Voorhis Dennis E. Kyle Peter J. Myler
author_sort	Isabelle Q. Phan
title	The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
title_short	The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
title_full	The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
title_fullStr	The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
title_full_unstemmed	The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
title_sort	transcriptome of balamuthia mandrillaris trophozoites for structure-guided drug design
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2f6501344d864a2aaccaf8376c641a80
work_keys_str_mv	AT isabelleqphan thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT christopherarice thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT justincraig thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT rooksanaenoorai thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT jacquelynrmcdonald thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT sandhyasubramanian thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT logantillery thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT lynnkbarrett thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT vijayshankar thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT jamescmorris thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT wesleycvanvoorhis thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT dennisekyle thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT peterjmyler thetranscriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT isabelleqphan transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT christopherarice transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT justincraig transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT rooksanaenoorai transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT jacquelynrmcdonald transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT sandhyasubramanian transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT logantillery transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT lynnkbarrett transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT vijayshankar transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT jamescmorris transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT wesleycvanvoorhis transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT dennisekyle transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign AT peterjmyler transcriptomeofbalamuthiamandrillaristrophozoitesforstructureguideddrugdesign
_version_	1718442604796837888

The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design

Ejemplares similares