Synthesis of novel ciprofloxacin-avibactam conjugates for the development of second-generation non-/3-lactam-/3-lactamase inhibitors

To overcome the antibiotic resistance challenge, we synthesized a novel class of conjugates based on ciprofloxacin and avibactam, covalently linked by diverse amino acids. In vitro studies of these conjugates have shown improved antibacterial efficacy of avibactam when used alone against some ESKAPE pathogens, i.e., S. aureus, E. coli, and A. baumannii. Further, ceftazidime was screened in combination with all conjugates and found to be less synergistically effective than avibactam-ceftazidime co-dosing against K. pneumoniae and E. coli bacterial strains. Subsequently, the top-ranked active conjugates were investigated against the commercially available /3-lactamase-II (Penicillinase from Bacillus cereus) through in vitro studies. These studies elucidated two conjugates i.e, 9 (IC50 = 1.69 +/- 0.35 nM) and 24b (IC50 = 57.37 +/- 5.39 nM), which have higher inhibition profile than avibactam (IC50 = 141.08 +/- 12.20 nM). These outcomes allude to avibactam integration with ciprofloxacin is a novel and fruitful approach to discovering clinically valuable next-generation non-/3-lactam-/3-lactamase inhibitors.