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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 Balasubramani, G. L.
Rajput, Rinky
Gupta, Manish
Dahiya, Pradeep
Thakur, Jitendra K.
Bhatnagar, Rakesh
Grover, Abhinav
 
Subject ATP hydrolysis
ATPase
DNA gyrase
DNA supercoiling
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 multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, 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 the 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. Furthermore, ATPase, and DNA supercoiling assays exhibited an IC50 values of 2.1–4.7 µM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 and 12 μM were observed for epirubicin and echinacoside, respectively, against Mtb. Our findings indicate that echinacoside and epirubicin targets 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.
 
Date 2020-11-25T09:52:16Z
2020-11-25T09:52:16Z
2020
 
Type Article
 
Identifier Biochemical Journal, 477(21): 4167–4190
https://portlandpress.com/biochemj/article-abstract/477/21/4167/226605/Structure-based-drug-repurposing-to-inhibit-the?redirectedFrom=fulltext
1470-8728
https://doi.org/10.1042/BCJ20200462
http://223.31.159.10:8080/jspui/handle/123456789/1126
 
Language en_US
 
Publisher Portland Press