Identification of an anti-TB compound targeting the tyrosyl-tRNA synthetase

Zhu, Ning; Lin, Yuan; Li, Dongsheng; Gao, Nana; Liu, Chang; You, Xuefu; Jiang, Jian‐Dong; Jiang, Wei; Si, Shuyi

doi:10.1093/jac/dkv110

Cited by 24 publications

(27 citation statements)

References 30 publications

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“…tuberculosis, [75,76] and polymorphisms in aspartyl-tRNA synthetase is associated with drug resistance mechanism in this pathogen [77]. Although, we predicted glyS is as an essential gene in M. tuberculosis, being a human homolog, it is not a suitable target.…”

Section: Tuberculosis Srna_1414mentioning

confidence: 83%

A potential link between tuberculosis and lung cancer through non-coding RNAs

Barh¹,

Tiwari²,

et al. 2017

Preprint

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; Tel/Fax: +91 944 955 0032 not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/188375 doi: bioRxiv preprint first posted online Sep. 13, 2017; 2 | P a g e ABSTRACT Pulmonary tuberculosis caused by Mycobacterium and lung cancer are two major causes of deaths worldwide and the former increases the risk of developing lung cancer. However, the precise molecular mechanism of Mycobacterium associated increased risk of lung cancer is not entirely understood. Here, using in silico approaches, we show that hsa-mir-21 and M. tuberculosis sRNA_1096 and sRNA_1414 could play important roles in the pathogenesis of both these diseases. Further, we postulated a "Genetic remittance" hypothesis where these sRNAs may play important roles. The sRNA_1096 could be involved in tuberculosis through multiple infectious processes, and if transferred to the host, it may activate the TLR8 mediated pro-metastatic inflammatory pathway by acting as a ligand to TLR8 similar to the mir-21 leading to lung tumorigenesis and chemo-resistance. Analogous to SH3GL1, it may also regulate cell cycle. On the other hand, sRNA_1414 is probably involved in survivability and drug response of the pathogen. However, it may be a metastatic factor for lung cancer providing EPS8L1 and SORBS1 like functions upon remittance. Further, all these three noncoding RNAs are predicted to act in rifampicin resistance in Mycobacterium. Currently, we are applying robust bioinformatics strategies and conducting experimental validations to confirm our in-silico findings and hypothesis.

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Section: Tuberculosis Srna_1414mentioning

confidence: 83%

A potential link between tuberculosis and lung cancer through non-coding RNAs

Barh¹,

Tiwari²,

et al. 2017

Preprint

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“…Further, we observed that sRNA_1414 might regulate drug transporter activity. Aspartyl-tRNA synthetase and tyrosyl-tRNA synthetase are important drug targets in M. tuberculosis [ 75 , 76 ] and polymorphisms in aspartyl-tRNA synthetase is associated with drug resistance mechanism in this pathogen [ 77 ]. Although, we predicted glyS is as an essential gene in M. tuberculosis, being a human homolog, it is not a suitable target.…”

Section: Discussionmentioning

confidence: 99%

Linking common non-coding RNAs of human lung cancer and M. tuberculosis

et al. 2018

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Lung cancer and pulmonary tuberculosis caused by Mycobacterium are two major causes of deaths worldwide. Tuberculosis linked lung cancer is known. However, the precise molecular mechanism of Mycobacterium associated increased risk of lung cancer is not understood. We report 45 common human miRNAs deregulated in both pulmonary tuberculosis and lung cancer. We show that sRNA_1096 and sRNA_1414 from M. tuberculosis have sequence homology with human mir-21. Hence, the potential role of these three small non-coding RNAs in rifampicin resistance in pulmonary tuberculosis is implied. Further, the linking of sRNA_1096 and sRNA_1414 from M. tuberculosis with the host lung tumorigenesis is inferred. Nonetheless, further analysis and validation is required to associate these three non-coding RNAs with Mycobacterium associated increased risk of lung cancer.

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“…Nonetheless, a recent publication revealed that DHQS is the main target of IMB-T130 ( Figure 7) [54]. This promising molecule exhibited an IC 50 of 2.7 µM and a MIC of 312 ng/mL against M. smegmatis, a 1.36 log reduction in the growth of intracellular mycobacteria infecting mouse macrophages, with low toxicity towards human embryonic kidney 293 and HeLa cells [55], showing this enzymes' potential as a druggable candidate. The chemical mechanism of E. coli DHQS was thoroughly investigated, dissecting each of the steps using substrate analogues to examine the early and late steps of the reaction, which arebinding to the enzyme, C5 oxidation by enzyme-bound NAD + , C6 enolization, β-elimination of the phosphate group, reduction at C5 regenerating NAD + , pyranose ring opening, and, finally, an aldol intramolecular reaction [47,48].…”

Section: -Dehydroquinate Synthase (Arob Coding Sequence; Ec 4234)mentioning

confidence: 95%

“…Nonetheless, a recent publication revealed that DHQS is the main target of IMB-T130 ( Figure 7) [54]. This promising molecule exhibited an IC50 of 2.7 μM and a MIC of 312 ng/mL against M. smegmatis, a 1.36 log reduction in the growth of intracellular mycobacteria infecting mouse macrophages, with low toxicity towards human embryonic kidney 293 and HeLa cells [55], showing this enzymes' potential as a druggable candidate.…”

Section: -Dehydroquinate Synthase (Arob Coding Sequence; Ec 4234)mentioning

confidence: 95%

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

et al. 2020

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Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.

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Identification of an anti-TB compound targeting the tyrosyl-tRNA synthetase

Abstract: IMB-T130 inhibits the growth of MDR-TB and XDR-TB by targeting MtTyrRS. Because of its low cytotoxicity against mammalian cells, IMB-T130 is a promising new agent against drug-resistant M. tuberculosis.

Cited by 24 publications

References 30 publications

A potential link between tuberculosis and lung cancer through non-coding RNAs

A potential link between tuberculosis and lung cancer through non-coding RNAs

Linking common non-coding RNAs of human lung cancer and M. tuberculosis

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

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