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.

Automated summary

In order to combat antibiotic resistance, a novel class of conjugates based on ciprofloxacin and avibactam were synthesized and found to have improved antibacterial efficacy against certain pathogens. Combination studies with ceftazidime showed less synergistic effect compared to avibactam-ceftazidime co-dosing. Furthermore, two conjugates exhibited higher inhibition profile against β-lactamase-II compared to avibactam, suggesting the integration of avibactam with ciprofloxacin is a promising approach for next-generation non-β-lactam-β-lactamase inhibitors.