# The Difluoroboranyl-Fluoroquinolone Derivative “7a” Inhibits Bacterial DNA Gyrase and Exhibits Potent Activity Against Ciprofloxacin-Resistant S. aureus In Vitro and In Vivo Using an Acute Pneumonia Model

## TL;DR

A new compound called 7a effectively fights antibiotic-resistant S. aureus in lab and animal tests by inhibiting bacterial DNA gyrase.

## Contribution

Compound 7a, a difluoroboranyl-fluoroquinolone, shows potent activity against ciprofloxacin-resistant S. aureus both in vitro and in vivo.

## Key findings

- Compound 7a had MIC and MBC values of 0.25 μg/mL against S. aureus.
- 7a reduced pneumonic tissue in infected mice by 1.99% without causing toxicity.
- DNA gyrase inhibition by 7a was confirmed through plasmid electrophoresis.

## Abstract

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 7a, a difluoroboranyl-fluoroquinolone that previously demonstrated activity against sensitive strains. Methods: The minimum inhibitory (MIC) and bactericidal (MBC) concentrations of compound 7a were determined against Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli. The selective development of ciprofloxacin-resistant S. aureus was 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 7a (80 mg/kg/day) was assessed in a murine pneumonia model induced by ciprofloxacin-resistant S. aureus. DNA gyrase inhibition was confirmed through plasmid electrophoresis assays in E. coli DH5-α cells. Results: Compound 7a exhibited both MIC and MBC values of 0.25 μg/mL, while ciprofloxacin-resistant S. aureus strains 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. In vivo, 7a 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: Compound 7a evidenced activity against ciprofloxacin-resistant S. aureus in vitro and reduced infection progression in vivo. It also displays favorable drug-like properties, low predicted toxicity, and DNA gyrase inhibition.