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J Med Chem. 2016 Jun 9;59(11):5542-54. doi: 10.1021/acs.jmedchem.6b00660. Epub 2016 May 20.

Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening.

Author information

1
The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.
2
Department of Chemistry, UiT The Arctic University of Norway , 9037 Tromsø, Norway.

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.

PMID:
27165692
DOI:
10.1021/acs.jmedchem.6b00660
[Indexed for MEDLINE]

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