ZAB260: A novel and potent antibacterial agent targeting DNA gyrase

DNA gyrase and topoisomerase IV are well-established targets for antibiotics. These enzymes play crucial roles in managing the topology of DNA, which is essential for bacterial survival. ZAB260, an inhibitor of bacterial DNA gyrase, is a dihydroquinoline carbonitrile-based antibacterial agent, which has potent antimicrobial activity against susceptible and drug-resistant pathogens. The MIC 90 for ZAB260 against methicillin resistant S. aureus , S. pyogens , S. pneumoniae , E . coli and A. baumannii were observed at 0.125 µg/ml, 0.25 µg/ml, 1 µg/ml, 2 µg/ml and 2 µg/ml respectively. The in vitro activity was evaluated using time-kill kinetics, post-antibiotic effect (PAE), and sub-inhibitory effect. The time-kill curves could show the bactericidal activity at 4X and 8X MIC at 24 h against S. aureus and A. baumannii . The post-antibiotic effect was modest when it was tested against S. aureus (2 h) and A. baumannii (4 h). The PAE and sub-MIC effect (SME) for S. aureus and A. baumannii was extended for 16 h and > 8 h. Checkerboard analysis of ZAB260 with marketed antimicrobials (Tetracycline, Levofloxacin, Cefepime, Azithromycin, Colistin, Meropenem) showed additive effect against A. baumannii . ZAB260 was also tested in rat lung infection model at 6.25, 12, 25, 50 and 100 mg/kg dose and a dose dependent reduction in log CFU was observed. Thus, ZAB260 was identified as a bactericidal agent with moderate post-antibiotic effect (PAE) and an extended PAE-sub-MIC effect (PAE-SME). It also showed a reduction of over 4 log CFU in rat lung infection model. These findings warrant further investigation for potential use in treating infections caused by these pathogens. • NBTIs binds to the site different from quinolones, hence would evade the existing quinolone induced resistance. • ZAB260 demonstrated potent antibacterial activity against MDR strains (active against both A. baumannii and S. aureus ). • ZAB260 showed dose dependent reduction in log CFU in rat lung infection model model.