title: Permeation through the cell membrane of a boron-based β-lactamase inhibitor.
abstract: Bacteria express beta-lactamases to counteract the beneficial action of antibiotics. Benzo[b]-thiophene-2-boronic acid (BZB) derivatives are β-lactamase inhibitors and, as such, promising compounds to be associated with β-lactam antibacterial therapies. The uncharged form of BZB, in particular, is suggested to diffuse through the outer membrane of gram negative bacteria. In this study, through the combination of electrophysiological experiments across reconstituted PC/n-decane bilayers and metadynamics-based free energy calculations, we investigate the permeation mechanism of boronic compounds. Our experimental data establish that BZB passes through the membrane, while computer simulations provide hints for the existence of an aqueous, water-filled monomolecular channel. These findings provide new perspectives for the design of boronic acid derivatives with high membrane permeability.
authors.affiliation: Modeling & Simulation Lab Department of Studies on Structures, University Roma Tre, Roma, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Minozzi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Roland
authors.initials: R
authors.lastname: Benz
authors.forename: Maria P
authors.initials: MP
authors.lastname: Costi
authors.forename: Alberto
authors.initials: A
authors.lastname: Venturelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D015195:Drug Design; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018440:beta-Lactam Resistance / Q000187:drug effects; D065093:beta-Lactamase Inhibitors
chemical_list: D001426:Bacterial Proteins; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D013876:Thiophenes; C115588:benzo(b)thiophene-2-boronic acid; D065093:beta-Lactamase Inhibitors; C028694:1-palmitoyl-2-oleoylphosphatidylcholine