Article
作者: Pang, Jing ; Tang, Sheng ; Wang, Xiukun ; Guo, Zhihao ; Zhang, Jingpu ; Lu, Xi ; Fan, Tianyun ; You, Xuefu ; Wang, Yanxiang ; Li, Zhiwen ; Song, Danqing ; Li, Yinghong ; Zhang, Rui ; Ma, Xican ; Hu, Xinxin ; Fu, Haigen ; Liu, Yonghua
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.
