The binding of free and copper-complexed fluoroquinolones to OmpF porins: an experimental and molecular docking study

Bacterial resistance is a critical public health issue and the development of alternative antibiotics to counteract this problem is an urgent matter. Fluoroquinolones are widely used antibiotics and numerous cases of bacterial resistance to these drugs have already been reported. One important mechanism of resistance is the decrease of the permeability of the bacterial membrane to antibiotics by mutation of the OmpF porin. Fluoroquinolone complexation with copper and a nitrogen-donor heterocyclic ligand is an approach developed to counteract this mechanism of bacterial resistance. The binding of antibiotics to the constriction zone residues of porins has been shown to be essential for their influx across the channel. In the present work, the interaction of sparfloxacin, ciprofloxacin and their respective copper ternary complexes with the outer-membrane protein F (OmpF) porin was studied to further explore the channel selectivity for each of these molecules. Surface plasmon resonance was used to determine the association constants between the drugs and the OmpF protein and molecular docking was used to further analyze the interaction between them. The results support a higher affinity of free fluoroquinolones to the constriction zone of the OmpF channel, when compared to the respective copper-complexes. The findings of this work provide insights that will be helpful to proceed with the study of metal-complexes as alternatives to free fluoroquinolones in resistant infections, avoiding the high-cost and time-consuming processes of discovering and designing new antibiotics.