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

Zhiwen LI; Zhihao Guo; Xi LU; Xican MA; Xiukun Wang; Rui Zhang; Xinxin HU; Yanxiang Wang; Jing Pang; Tianyun Fan; Yonghua Liu; Sheng Tang; Haigen FU; Jingpu Zhang; Yinghong LI; Xuefu You; Danqing Song

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

Author: Zhiwen LI ¹ ; Zhihao GUO ¹ ; Xi LU ¹ ; Xican MA ¹ ; Xiukun WANG ¹ ; Rui ZHANG ¹ ; Xinxin HU ¹ ; Yanxiang WANG ¹ ; Jing PANG ¹ ; Tianyun FAN ¹ ; Yonghua LIU ¹ ; Sheng TANG ¹ ; Haigen FU ¹ ; Jingpu ZHANG ¹ ; Yinghong LI ¹ ; Xuefu YOU ¹ ; Danqing SONG ¹
Author Information

1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Publication Type:Journal Article
Keywords: Chemoproteomic; Drug-resistant gram-negative bacteria; Dual mode of action; Monobactam; Synergistic effect
From: Acta Pharmaceutica Sinica B 2023;13(7):3067-3079
CountryChina
Language:English
Abstract: 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.