Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide

Abstract Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally,...

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Autores principales:	Hai-Nan Zhang, Zhao-Wei Xu, He-Wei Jiang, Fan-Lin Wu, Xiang He, Yin Liu, Shu-Juan Guo, Yang Li, Li-Jun Bi, Jiao-Yu Deng, Xian-En Zhang, Sheng-Ce Tao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df874065a394449c8edcc905acde5f89
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spelling	oai:doaj.org-article:df874065a394449c8edcc905acde5f892021-12-02T15:04:51ZCyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide10.1038/s41598-017-06289-72045-2322https://doaj.org/article/df874065a394449c8edcc905acde5f892017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06289-7https://doaj.org/toc/2045-2322Abstract Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally, with existing severe problem of ETH resistance. ETH is a prodrug, which is activated by Etha inside M.tb, and etha is transcriptionally repressed by Ethr. We found that c-di-GMP could bind Ethr, enhanced the binding of Ethr to the promoter of etha, and then repressed the transcription of etha, thus caused resistance of M.tb to ETH. Through docking analysis and in vitro validation, we identified that c-di-GMP binds 3 amino acids of Ethr, i.e., Q125, R181 and E190, while the first 2 were the major binding sites. Homology analysis showed that Ethr was highly conservative among mycobacteria. Further docking analysis showed that c-di-GMP preferentially bound proteins of TetR family at the junction hole of symmetric dimer or tetramer proteins. Our results suggest a possible drug-resistance mechanism of ETH through the regulation of Ethr by c-di-GMP.Hai-Nan ZhangZhao-Wei XuHe-Wei JiangFan-Lin WuXiang HeYin LiuShu-Juan GuoYang LiLi-Jun BiJiao-Yu DengXian-En ZhangSheng-Ce TaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hai-Nan Zhang Zhao-Wei Xu He-Wei Jiang Fan-Lin Wu Xiang He Yin Liu Shu-Juan Guo Yang Li Li-Jun Bi Jiao-Yu Deng Xian-En Zhang Sheng-Ce Tao Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
description	Abstract Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally, with existing severe problem of ETH resistance. ETH is a prodrug, which is activated by Etha inside M.tb, and etha is transcriptionally repressed by Ethr. We found that c-di-GMP could bind Ethr, enhanced the binding of Ethr to the promoter of etha, and then repressed the transcription of etha, thus caused resistance of M.tb to ETH. Through docking analysis and in vitro validation, we identified that c-di-GMP binds 3 amino acids of Ethr, i.e., Q125, R181 and E190, while the first 2 were the major binding sites. Homology analysis showed that Ethr was highly conservative among mycobacteria. Further docking analysis showed that c-di-GMP preferentially bound proteins of TetR family at the junction hole of symmetric dimer or tetramer proteins. Our results suggest a possible drug-resistance mechanism of ETH through the regulation of Ethr by c-di-GMP.
format	article
author	Hai-Nan Zhang Zhao-Wei Xu He-Wei Jiang Fan-Lin Wu Xiang He Yin Liu Shu-Juan Guo Yang Li Li-Jun Bi Jiao-Yu Deng Xian-En Zhang Sheng-Ce Tao
author_facet	Hai-Nan Zhang Zhao-Wei Xu He-Wei Jiang Fan-Lin Wu Xiang He Yin Liu Shu-Juan Guo Yang Li Li-Jun Bi Jiao-Yu Deng Xian-En Zhang Sheng-Ce Tao
author_sort	Hai-Nan Zhang
title	Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
title_short	Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
title_full	Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
title_fullStr	Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
title_full_unstemmed	Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide
title_sort	cyclic di-gmp regulates mycobacterium tuberculosis resistance to ethionamide
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/df874065a394449c8edcc905acde5f89
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Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide

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