Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

金黄色葡萄球菌感染历史上一直使用 β-内酰胺类抗生素治疗。然而，这些抗生素在耐甲氧西林的金黄色葡萄球菌中通过获得 bla 和 mec 操纵子而过时了。BlaR 和/或 MecR 的传感器结构域检测到 β-内酰胺类抗生素的存在，并将信息传输到细胞质，导致抗生素耐药基因的去抑制。我们假设传感器域的抑制会关闭这个反应系统，并且 β-内酰胺敏感性会恢复。对 1100 万种化合物进行计算机检索，得出了基于苯并咪唑的搜索结果，并最终发现了硼酸盐 4。4 的 X 射线结构与 BlaR 的活性位点丝氨酸共价结合。化合物 4 将苯唑西林和美罗培南对耐甲氧西林金黄色葡萄球菌菌株的活性提高了 16 至 4,096 倍。4 与苯唑西林或美罗培南的组合在感染的小鼠中显示出疗效，验证了该策略。