A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4–512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

一系列新的单菌素磺酸盐被不断合成并评估其对革兰氏阴性菌的抗菌功效。化合物33a (IMBZ18G)在体外和体内对临床难治性多重耐药 (MDR) 革兰氏阴性菌株非常有效，具有高度药物样性质。棋盘实验显示其与β-内酰胺酶抑制剂阿维巴坦具有显着的协同作用，针对MDR肠杆菌的MIC值降低达4-512倍。X射线共晶和化学蛋白质组学分析表明， 33a的抗MDR细菌作用源于对常见PBP3和一些A类和C类β-内酰胺酶的双重抑制。因此，作为潜在创新候选药物的33a单药和33a -avibactam 组合在治疗产生β-内酰胺酶的 MDR 革兰氏阴性细菌感染方面的临床前研究正在积极进行。