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

doi:10.1016/j.apsb.2023.03.002

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

Acta Pharm Sin B. 2023 Jul;13(7):3067-3079. doi: 10.1016/j.apsb.2023.03.002. Epub 2023 Mar 7.

Authors

Zhiwen Li¹, Zhihao Guo¹, Xi Lu¹, Xican Ma¹, Xiukun Wang¹, Rui Zhang¹, Xinxin Hu¹, Yanxiang Wang¹, Jing Pang¹, Tianyun Fan¹, Yonghua Liu¹, Sheng Tang¹, Haigen Fu¹, Jingpu Zhang¹, Yinghong Li¹, Xuefu You¹, Danqing Song¹

Affiliation

¹ Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

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.

Keywords: Chemoproteomic; Drug-resistant gram-negative bacteria; Dual mode of action; Monobactam; Synergistic effect.