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 IC50 values 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1680-1690 |
| Number of pages | 11 |
| Journal | Journal of Chemical Information and Modeling |
| Volume | 62 |
| Issue number | 7 |
| Early online date | 29 Mar 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 29 Mar 2022 |
Bibliographical note
Funding Information:This research was supported by the Health Systems Research Institute (HSRI.60.083), the Thailand Research Fund (RSA5980057 and MRG6180147), the Office of the Higher Education Commission, Center of Excellence for Innovation in Chemistry (PERCH-CIC), and Ubon Ratchathani University. The financial support from Royal Golden Jubilee Ph.D. Program to B.P. (PHD/0115/2560) and B.K. (PHD/0132/2559) is gratefully acknowledged. The Thailand Graduate Institute of Science and Technology (SCA-CO-2561-6946-TH and SCA-CO-2563-12135-TH) is acknowledged for financial support to P.T. and N.P., respectively. A.J.M. and J.S. acknowledge funding from the BristolBridge antimicrobial resistance network (EPSRC EP/M027546/1). We thank CCP-BioSim (grant no EP/M022609/1) for funding. Ubon Ratchathani University, the NSTDA Supercomputer Center (ThaiSC), NECTEC, and the University of Bristol are gratefully acknowledged for supporting this research.
Funding Information:
CCP-BioSim (EP/M022609/1), Center of Excellence for Innovation in Chemistry (PERCH-CIC), The Royal Golden Jubilee Ph.D. Program (PHD/0115/2560 and PHD/0132/2559). The BristolBridge antimicrobial resistance network-(EPSRC EP/M027546/1). The Health Systems Research Institute (HSRI.60.083). The Thailand Graduate Institute of Science and Technology (TGIST) (SCA-CO-2561-6946-TH and SCA-CO-2563-12135-TH). The Thailand Research Fund (RSA5980057). The Thailand Research Fund and the Office of the Higher Education Commission (MRG6180147). Ubon Ratchathani University.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
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