Structure Guided Discovery of Novel Pan Metallo- β -Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration

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作   者：

Hicks, Jacqueline D.;  Fischmann, Thierry;  Mirza, Asra;  Dayananth, Priya;  Painter, Ronald E.;  Villafania, Artjohn;  Garlisi, Charles G.;  Zhang, Rumin;  Mayhood, Todd W.;  Si, Qian;  Li, Nianyu;  Amin, Rupesh P.;  Chen, Feifei;  Dejesus, Reynalda Keh;  Regan, Christopher P.;  Regan, Hillary;  Lin, Xinjie;  Wu, Jin;  Leithead, Andrew;  Pollack, Scott R.;  Scott, Jack D.;  Nargund, Ravi P.;  Therien, Alex G.;  Black, Todd;  Young, Katherine;  Pasternak, Alexander;  Bhatt, Bhavana;  Dong, Shuzhi;  Zhao, Zhiqiang;  Tang, Haiqun;  Li, Guoqing;  Pan, Jianping;  Gu, Xin;  Jiang, Jinlong;  Xiao, Li;  Scapin, Giovanna;  Hunter, David N.;  Yang, Dexi;  Huang, Yuhua;  Bennett, Frank;  Yang, Shu-Wei;  Mandal, Mihirbaran;  Tang, Haifeng;  Su, Jing;  Tudge, Clare;  Ding, Fa-Xiang;  Lombardo, Matthew; 

作者机构：

Merck & Co Inc; 

关键词：

OUTER-MEMBRANE;  EVOLUTION;  RESISTANCE;  OPTIMIZATION;  MECHANISMS;  TRENDS; 

期刊名称：

Journal of Medicinal Chemistry

i s s n：

0022-2623

年卷期：

2024 年 67 卷 5 期

页   码：

3400-3418

页   码：

摘   要：

The use of beta-lactam (BL) and beta-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-beta-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.