title: Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening.
abstract: The spread of antibiotic resistant bacteria is a global threat that shakes the foundations of modern healthcare. β-Lactamases are enzymes that confer resistance to β-lactam antibiotics in bacteria, and there is a critical need for new inhibitors of these enzymes for combination therapy together with an antibiotic. With this in mind, we have screened a library of 490 fragments to identify starting points for the development of new inhibitors of the class D β-lactamase oxacillinase-48 (OXA-48) through surface plasmon resonance (SPR), dose-rate inhibition assays, and X-ray crystallography. Furthermore, we have uncovered structure-activity relationships and used alternate conformations from a crystallographic structure to grow a fragment into a more potent compound with a KD of 50 μM and an IC50 of 18 μM.
authors.affiliation: The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
authors.forename: Bjarte Aarmo
authors.initials: BA
authors.lastname: Lund
authors.affiliation: The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
authors.forename: Tony
authors.initials: T
authors.lastname: Christopeit
authors.affiliation: Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
authors.forename: Yngve
authors.initials: Y
authors.lastname: Guttormsen
authors.affiliation: Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
authors.forename: Annette
authors.initials: A
authors.lastname: Bayer
authors.affiliation: The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
authors.forename: Hanna-Kirsti S
authors.initials: HK
authors.lastname: Leiros
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases