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

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.