Cepharanthine as a potential Fis inhibitor enhances Enrofloxacin efficacy against Pasteurella multocida

Pasteurella multocida, a primary bacterial pathogen responsible for bovine respiratory diseases, has developed resistance to multiple antibiotics, including fluoroquinolones, and is also an important zoonotic pathogen. Previous studies have demonstrated that Fis protein plays a critical role in bacterial virulence and antibiotic resistance formation. In resistant strains, Fis expression is upregulated and deletion of this gene significantly delays the development of fluoroquinolone resistance. Thus, Fis represents a potential target protein of antibiotic resistance inhibitors. Through meticulous molecular docking and dynamics simulation studies, we have identified that cepharanthine as a potential inhibitor of Fis. The combination of cepharanthine and enrofloxacin successfully inhibits the development of fluoroquinolone resistance in Pasteurella multocida, with the fractional inhibitory concentration index indicating synergistic antimicrobial effect. Based on energy metabolism measurements and transcriptome sequencing analyses, we consider cepharanthine as a potential Fis inhibitor that may play a role in multiple biological processes of Pasteurella multocida regulated by Fis protein, resulting in a synergistic antibacterial response. Cepharanthine is a potent Fis inhibitor and its combination with enrofloxacin presents a highly promising therapeutic approach for combatting Pasteurella multocida infections.