Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

• Published in: Acta pharmaceutica Sinica. B Vol. 13; no. 7; pp. 3067 - 3079
• Main Authors: Li, Zhiwen, Guo, Zhihao, Lu, Xi, Ma, Xican, Wang, Xiukun, Zhang, Rui, Hu, Xinxin, Wang, Yanxiang, Pang, Jing, Fan, Tianyun, Liu, Yonghua, Tang, Sheng, Fu, Haigen, Zhang, Jingpu, Li, Yinghong, You, Xuefu, Song, Danqing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2023; Elsevier
• Subjects: Chemoproteomic; Drug-resistant gram-negative bacteria; Dual mode of action; Monobactam; Original; Synergistic effect; Chemoproteomic; Drug-resistant gram-negative bacteria; Synergistic effect; Monobactam; Dual mode of action
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.03.002

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. IMBZ18G is highly effective against MDR Gram-negative bacteria, with the dual inhibition on PBP3 and class A and C β-lactamases. IMBZ18G-avibactam combination further broadens the antibacterial application of IMBZ18G. [Display omitted]