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.

抗生素耐药细菌的传播是撼动现代医疗体系根基的全球性威胁。β-内酰胺酶（β-Lactamases）是赋予细菌对β-内酰胺类抗生素耐药性的酶类，当前亟需开发可与抗生素联用的该类酶新型抑制剂以开展联合疗法。基于此，我们通过表面等离子体共振（surface plasmon resonance，SPR）、剂量速率抑制实验以及X射线晶体学，筛选了包含490个片段的小分子库，以寻找D类β-内酰胺酶苯唑西林酶-48（oxacillinase-48，OXA-48）抑制剂开发的起始先导位点。此外，我们阐明了该类抑制剂的构效关系，并借助晶体结构中的交替构象，将初始片段衍生为活性更强的化合物，其解离常数（KD）为50 μM，半最大抑制浓度（IC50）为18 μM。