Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Sci Rep. 2017 Jul 19;7(1):5860. doi: 10.1038/s41598-017-06289-7.

Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide.

Author information

1
Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.
2
National Key Laboratory of Biomacromolecules, Key Laboratory of Non-Coding RNA and Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
3
TB Healthcare Biotechnology Co., Ltd., Foshan, Guangdong, 528000, China.
4
School of Stomatology and Medicine, Foshan University, Foshan, 528000, Guangdong, China.
5
Guangdong Province Key Laboratory of TB Systems Biology and Translational Medicine, Foshan, 528000, China.
6
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
7
Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China. taosc@sjtu.edu.cn.
8
School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China. taosc@sjtu.edu.cn.
9
State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, 200240, China. taosc@sjtu.edu.cn.

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.

PMID:
28725053
PMCID:
PMC5517500
DOI:
10.1038/s41598-017-06289-7
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center