Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis
Issued Date
2022-04-11
Resource Type
ISSN
15499596
eISSN
1549960X
Scopus ID
2-s2.0-85127914992
Pubmed ID
35347987
Journal Title
Journal of Chemical Information and Modeling
Volume
62
Issue
7
Start Page
1680
End Page
1690
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Chemical Information and Modeling Vol.62 No.7 (2022) , 1680-1690
Suggested Citation
Pakamwong B., Thongdee P., Kamsri B., Phusi N., Kamsri P., Punkvang A., Ketrat S., Saparpakorn P., Hannongbua S., Ariyachaokun K., Suttisintong K., Sureram S., Kittakoop P., Hongmanee P., Santanirand P., Spencer J., Mulholland A.J., Pungpo P. Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis. Journal of Chemical Information and Modeling Vol.62 No.7 (2022) , 1680-1690. 1690. doi:10.1021/acs.jcim.1c01390 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/84094
Title
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis
Author's Affiliation
Chulabhorn Research Institute
Ramathibodi Hospital
Nakhon Phanom University
Vidyasirimedhi Institute of Science and Technology
Ubon Ratchathani University
Chulabhorn Royal Academy
Kasetsart University
University of Bristol
Thailand National Nanotechnology Center
Ministry of Higher Education, Science, Research and Innovation
Ramathibodi Hospital
Nakhon Phanom University
Vidyasirimedhi Institute of Science and Technology
Ubon Ratchathani University
Chulabhorn Royal Academy
Kasetsart University
University of Bristol
Thailand National Nanotechnology Center
Ministry of Higher Education, Science, Research and Innovation
Other Contributor(s)
Abstract
Mycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biological assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compound library (www.specs.net). Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 μg/mL. The two compounds inhibited DNA gyrase ATPase activity with IC50values of 2.69 and 2.46 μM, respectively, suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compounds G24 and G26 bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by molecular dynamics simulations followed by pharmacophore mapping analysis, showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compound lipophilicity by increasing the polarity of these tails then presents a likely route to improving the solubility and activity. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.