Permeation through the cell membrane of a boron-based β-lactamase inhibitor.

Bacteria express beta-lactamases to counteract the beneficial action of antibiotics. Benzo[b]-thiophene-2-boronic acid (BZB)derivatives are b-lactamase inhibitors and, as such, promising compounds to be associated with b-lactam antibacterialtherapies. The uncharged form of BZB, in particular, is suggested to diffuse through the outer membrane of Gram negativebacteria. In this study, through the combination of electrophysiological experiments across reconstituted PC/n-decanebilayers and metadynamics-based free energy calculations, we investigate the permeation mechanism of boroniccompounds. Our experimental data establish that BZB passes through the membrane, while computer simulations providehints for the existence of an aqueous, water-filled monomolecular channel. These findings provide new perspectives for thedesign of boronic acid derivatives with high membrane permeability.