The Difluoroboranyl-Fluoroquinolone Derivative "7a" Inhibits Bacterial DNA Gyrase and Exhibits Potent Activity Against Ciprofloxacin-ResistantIn Vitro and In Vivo Using an Acute Pneumonia Model.

Abstract

UNLABELLED: According to the World Health Organization, antibiotic research remains insufficient, emphasizing the urgent need for new active molecules, particularly against resistant bacteria. Based on known antibacterial scaffolds, new fluoroquinolone derivatives have been synthesized by our research group, including compound, a difluoroboranyl-fluoroquinolone that previously demonstrated activity against sensitive strains. METHODS: The minimum inhibitory (MIC) and bactericidal (MBC) concentrations of compoundwere determined against,, and. The selective development of ciprofloxacin-resistantwas induced by reseeding the isolate on seven consecutive days with an antibiotic concentration that was not capable of inhibiting its development. Pharmacokinetic and toxicological properties were predicted using SwissADME, Way2Drug, and molecular docking (AutoDock Vina). In vivo toxicity was evaluated in BALB/c mice through histopathological liver and kidney analysis and serum biochemical markers. The antibacterial efficacy of(80 mg/kg/day) was assessed in a murine pneumonia model induced by ciprofloxacin-resistant. DNA gyrase inhibition was confirmed through plasmid electrophoresis assays inDH5-α cells. RESULTS: Compoundexhibited both MIC and MBC values of 0.25 μg/mL, while ciprofloxacin-resistantstrains did not exhibit a detectable MIC within the concentration range tested (up to 1024 μg/mL). In silico predictions revealed favorable ADME profiles, low toxicity, and strong interaction with DNA gyrase.,showed no signs of hepatotoxicity or nephrotoxicity and effectively reduced pneumonic tissue to 1.99% in infected mice. Electrophoretic assays confirmed DNA gyrase inhibition consistent with the mechanism of fluoroquinolones. CONCLUSIONS: Compoundevidenced activity against ciprofloxacin-resistantin vitro and reduced infection progression in vivo. It also displays favorable drug-like properties, low predicted toxicity, and DNA gyrase inhibition.