title: Optimizing cell permeation of an antibiotic resistance inhibitor for improved efficacy.
abstract: Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C beta-lactamase AmpC and potentiates the activity of beta-lactam antibiotics in bacteria that express this and related enzymes. As is often true, the potency of compound 1 against the enzymes is much attenuated in cell culture against Gram negative bacteria, where the minimum inhibitor concentration of compound 1 is in the mid-micromolar range. Here, we modulated the properties of this lead to enhance its ability to cross the membrane, using a combination of X-ray crystallography, structure-based design, and application of physical models of outer membrane crossing. This strategy led us to derivatives with substantially improved permeability. Also, the greater solubility of these compounds allowed us to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of ceftazidime on resistant bacteria.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100, Modena, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Venturelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Tondi
authors.forename: Laura
authors.initials: L
authors.lastname: Cancian
authors.forename: Federica
authors.initials: F
authors.lastname: Morandi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.forename: Bernardetta
authors.initials: B
authors.lastname: Segatore
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Amicosante
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D007700:Kinetics; D008567:Membranes, Artificial; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D012995:Solubility; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D008567:Membranes, Artificial; D013876:Thiophenes; C525465:benzo(b)thiophene-2-ylboronic acid; C048795:AmpC beta-lactamases; D001618:beta-Lactamases