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

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 mu M). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 mu M) and f14 (IC50: 0.28 mu M). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4-8 mu g/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 mu M), 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.

Automated summary

Emerging drug resistance highlights the need for new and effective antibiotics. This study used a 4-hydroxy-2-quinolone fragment to search for potential GyrB inhibitors and identified a novel and potent inhibitor, f1, with promising activity against drug-resistant bacteria. Further structural modification resulted in two more potent GyrB inhibitors, f4 and f14. Compound f1 exhibited superior antibacterial activity against MRSA, low toxicity to cells, and metabolic stability.