Pros and cons of the tuberculosis drugome approach--an empirical analysis.

Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning...

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Autores principales:	Feng-Chi Chen, Yu-Chieh Liao, Jie-Mao Huang, Chieh-Hua Lin, Yih-Yuan Chen, Horng-Yunn Dou, Chao Agnes Hsiung
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21e6051bdf014324a0d33f1d7e509f80
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spelling	oai:doaj.org-article:21e6051bdf014324a0d33f1d7e509f802021-11-11T08:21:11ZPros and cons of the tuberculosis drugome approach--an empirical analysis.1932-620310.1371/journal.pone.0100829https://doaj.org/article/21e6051bdf014324a0d33f1d7e509f802014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24971632/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning of current drugs. However, the effectiveness of this approach has rarely been examined. Here we select the "TB drugome" approach--a protein structure-based method for drug repositioning for tuberculosis treatment--to (1) experimentally validate the efficacy of the identified drug candidates for inhibiting MTB growth, and (2) computationally examine how consistently drug candidates are prioritized, considering changes in input data. Twenty three drugs in the TB drugome were tested. Of them, only two drugs (tamoxifen and 4-hydroxytamoxifen) effectively suppressed MTB growth at relatively high concentrations. Both drugs significantly enhanced the inhibitory effects of three first-line anti-TB drugs (rifampin, isoniazid, and ethambutol). However, tamoxifen is not a top-listed drug in the TB drugome, and 4-hydroxytamoxifen is not approved for use in humans. Computational re-examination of the TB drugome indicated that the rankings were subject to technical and data-related biases. Thus, although our results support the effectiveness of the TB drugome approach for identifying drugs that can potentially be repositioned for stand-alone applications or for combination treatments for TB, the approach requires further refinements via incorporation of additional biological information. Our findings can also be extended to other structure-based drug repositioning methods.Feng-Chi ChenYu-Chieh LiaoJie-Mao HuangChieh-Hua LinYih-Yuan ChenHorng-Yunn DouChao Agnes HsiungPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e100829 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Feng-Chi Chen Yu-Chieh Liao Jie-Mao Huang Chieh-Hua Lin Yih-Yuan Chen Horng-Yunn Dou Chao Agnes Hsiung Pros and cons of the tuberculosis drugome approach--an empirical analysis.
description	Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning of current drugs. However, the effectiveness of this approach has rarely been examined. Here we select the "TB drugome" approach--a protein structure-based method for drug repositioning for tuberculosis treatment--to (1) experimentally validate the efficacy of the identified drug candidates for inhibiting MTB growth, and (2) computationally examine how consistently drug candidates are prioritized, considering changes in input data. Twenty three drugs in the TB drugome were tested. Of them, only two drugs (tamoxifen and 4-hydroxytamoxifen) effectively suppressed MTB growth at relatively high concentrations. Both drugs significantly enhanced the inhibitory effects of three first-line anti-TB drugs (rifampin, isoniazid, and ethambutol). However, tamoxifen is not a top-listed drug in the TB drugome, and 4-hydroxytamoxifen is not approved for use in humans. Computational re-examination of the TB drugome indicated that the rankings were subject to technical and data-related biases. Thus, although our results support the effectiveness of the TB drugome approach for identifying drugs that can potentially be repositioned for stand-alone applications or for combination treatments for TB, the approach requires further refinements via incorporation of additional biological information. Our findings can also be extended to other structure-based drug repositioning methods.
format	article
author	Feng-Chi Chen Yu-Chieh Liao Jie-Mao Huang Chieh-Hua Lin Yih-Yuan Chen Horng-Yunn Dou Chao Agnes Hsiung
author_facet	Feng-Chi Chen Yu-Chieh Liao Jie-Mao Huang Chieh-Hua Lin Yih-Yuan Chen Horng-Yunn Dou Chao Agnes Hsiung
author_sort	Feng-Chi Chen
title	Pros and cons of the tuberculosis drugome approach--an empirical analysis.
title_short	Pros and cons of the tuberculosis drugome approach--an empirical analysis.
title_full	Pros and cons of the tuberculosis drugome approach--an empirical analysis.
title_fullStr	Pros and cons of the tuberculosis drugome approach--an empirical analysis.
title_full_unstemmed	Pros and cons of the tuberculosis drugome approach--an empirical analysis.
title_sort	pros and cons of the tuberculosis drugome approach--an empirical analysis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/21e6051bdf014324a0d33f1d7e509f80
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Pros and cons of the tuberculosis drugome approach--an empirical analysis.

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