ZAB260: A novel and potent antibacterial agent targeting DNA gyrase

Abstract

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 MIC₉₀ 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.