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Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis

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Title Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
 
Creator GL, Balasubramani
Rajput, Rinky
Gupta, Manish
Dahiya, Pradeep
Thakur, Jitendra K.
Bhatnagar, Rakesh
Grover, Abhinav
 
Subject DNA gyrase
ATPase
DNA supercoiling
ATP hydrolysis
drug repurposing
Mycobacterium tuberculosis
 
Description Accepted date: October 08 2020
Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis H37Rv (Mtb), as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a potent binder of MtbGyrB47. Further, ATPase and DNA supercoiling assays exhibited IC50 values of 2.1-4.7 µM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 μM and 12 μM were observed for epirubicin and echinacoside, respectively against Mtb. Our findings indicate that echinacoside and epirubicin target mycobacterial DNA gyrase, inhibit its catalytic cycle, and retard mycobacterium growth. Further, these compounds exhibit potential scaffolds for optimizing novel anti-mycobacterial agents that can act on drug-resistant strains.
Authors thank the Jawaharlal Nehru University (JNU) for infrastructural support. AG is grateful to University Grants Commission (UGC), India for the Faculty Recharge position.
BGL acknowledges Indian Council of Medical Research (ICMR) for providing Senior
Research Fellowship (SRF No. BIC/11(15)/2015). RR acknowledges Department of Science
& Technology (DST) - Science and Engineering Research Board (SERB) for providing
National Post-Doctoral Fellowship (NPDF File No. PDF/2016/000196). Authors
acknowledge National Institute of Plant Genome Research (NIPGR) for Biacore T-200 SPR
facility.
 
Date 2020-10-13T09:36:45Z
2020-10-13T09:36:45Z
2020
 
Type Article
 
Identifier Biochemical Journal, (In Press)
0264-6021
https://doi.org/10.1042/BCJ20200462
https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20200462
http://223.31.159.10:8080/jspui/handle/123456789/1113
 
Language en_US
 
Format application/pdf
 
Publisher Portland Press