Back to Search
Start Over
Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
- Source :
- Biochemical Journal. 477:4167-4190
- Publication Year :
- 2020
- Publisher :
- Portland Press Ltd., 2020.
-
Abstract
- 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.
- Subjects :
- Antitubercular Agents
Microbial Sensitivity Tests
Pharmacology
Biochemistry
DNA gyrase
Mycobacterium tuberculosis
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Topoisomerase II Inhibitors
Glycosides
Molecular Biology
Epirubicin
030304 developmental biology
Adenosine Triphosphatases
0303 health sciences
biology
030306 microbiology
Circular Dichroism
Drug Repositioning
Cell Biology
Surface Plasmon Resonance
biology.organism_classification
Drug repositioning
chemistry
DNA Gyrase
Doxorubicin
Docking (molecular)
Drug Design
Echinacoside
DNA supercoil
Idarubicin
DrugBank
Mycobacterium
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 477
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....9315485cc3de20e4e846b9d052494640