Abstract / Summary
Abstract The rapid rise of antimicrobial resistance, especially in Staphylococcus aureus , highlights the urgent need for improved antibacterial agents. In 2019 alone, AMR caused an estimated 1.27 million deaths and contributed to nearly 5 million more globally. Here, we present the design, synthesis, and testing of modified ciprofloxacin analogs bearing nitrofuran, furan, and spirocyclic diamine moieties. Among these compounds, two showed a more than eight-fold increase in potency against ciprofloxacin-resistant S.aureus ISR14-002 compared to ciprofloxacin, demonstrating improved activity against a ciprofloxacin-resistant strain. In vivo testing using a Galleria mellonella infection model with S. aureus SG511 demonstrated that compound 12 conferred a survival benefit comparable to ciprofloxacin. Improved activity was most notable against Gram-positive bacteria, especially our target pathogen S. aureus . However, the spectrum of organism selectivity varied by analog, highlighting the effects of focused structural modification. These results suggest that the fluoroquinolone scaffold can be modified to circumvent ciprofloxacin resistance and expand its spectrum of activity, while retaining acceptable cellular toxicity.