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

  • J Med Chem. 2024 Feb 22. doi: 10.1021/acs.jmedchem.3c01614.
Shuzhi Dong  1 ,  Zhiqiang Zhao  1 ,  Haiqun Tang  1 ,  Guoqing Li  1 ,  Jianping Pan  1 ,  Xin Gu  1 ,  Jinlong Jiang  1 ,  Li Xiao  2 ,  Giovanna Scapin  2 ,  David N Hunter  1 ,  Dexi Yang  1 ,  Yuhua Huang  1 ,  Frank Bennett  1 ,  Shu-Wei Yang  1 ,  Mihirbaran Mandal  1 ,  Haifeng Tang  1 ,  Jing Su  1 ,  Clare Tudge  1 ,  Reynalda Keh deJesus  1 ,  Fa-Xiang Ding  1 ,  Matthew Lombardo  1 ,  Jacqueline D Hicks  1 ,  Thierry Fischmann  2 ,  Asra Mirza  3 ,  Priya Dayananth  4 ,  Ronald E Painter  4 ,  Artjohn Villafania  4 ,  Charles G Garlisi  4 ,  Rumin Zhang  4 ,  Todd W Mayhood  4 ,  Qian Si  4 ,  Nianyu Li  5 ,  Rupesh P Amin  5 ,  Bhavana Bhatt  5 ,  Feifei Chen  5 ,  Christopher P Regan  5 ,  Hillary Regan  5 ,  Xinjie Lin  6 ,  Jin Wu  6 ,  Andrew Leithead  7 ,  Scott R Pollack  8 ,  Jack D Scott  1 ,  Ravi P Nargund  1 ,  Alex G Therien  9 ,  Todd Black  3 ,  Katherine Young  3 ,  Alexander Pasternak  1
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 2. Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 3. Antibacterial/Antifungal, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 4. Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 5. Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 6. Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 7. Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 8. Discovery Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 9. Exploratory Science Center, Merck & Co., Inc., Cambridge, Massachusetts 02139, United States.
PMID: 38387069 DOI: 10.1021/acs.jmedchem.3c01614
Abstract

The use of β-lactam (BL) and β-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-β-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.

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