Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents

Abstract

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC₅₀: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC₅₀: 0.31 µM) and f14 (IC₅₀: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4–8 µg/mL), non-toxic to HUVEC and HepG2 (CC₅₀: approximately 50 µM), and metabolically stable (t_1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.

Keywords:

• Antibiotic resistance
• MRSA
• antibacterial agent
• DNA Gyrase inhibitors
• computer-aided drug design

Acknowledgements

The authors thank OpenEye Scientific Software Inc. for providing a free academic license for their software.

Author contributions

J. X. conceived and supervised the project. J.X. designed the experiments. W.X, J.K., and J.X. contributed to the computational modelling, including substructure search, molecular docking, prediction of metabolic stability. W.X., Y. W., X.L, X.L. performed chemical synthesis. J.P., K. W., Z.H., X.Y., and H.Z. contributed to the bioassays. W.X. and J.X. wrote the manuscript with the input from the others. J.X. and S.W. assume responsibility for the manuscript in its entirety.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Additional information

Funding

This work was supported by the CAMS Innovation Fund for Medical Sciences [Grant No. 2021-I2M-1–069], Fundamental Research Program of Shanxi Province [Grant No. 20210302124300], the Shanxi Bethune Hospital Scientific Research Fund for Talent Recruitment [Grant No. 2021RC008], “Universities and Colleges Key Programs for Foreign Talent” of State Administration of Foreign Experts Affairs P.R. China [Grant No. T2018042].