2. Academic Validation
  3. Discovery of sulfone containing metallo-β-lactamase inhibitors with reduced bacterial cell efflux and histamine release issues

Discovery of sulfone containing metallo-β-lactamase inhibitors with reduced bacterial cell efflux and histamine release issues

  • Bioorg Med Chem Lett. 2024 Oct 11:114:129989. doi: 10.1016/j.bmcl.2024.129989.
Frank Bennett 1,  Yuhua Huang 2,  Shuzhi Dong 2,  Jinlong Jiang 2,  David Hunter 2,  Zhiqiang Zhao 2,  Xin Gu 2,  Jack D Scott 2,  Haiqun Tang 2,  Dexi Yang 2,  Li Xiao 3,  Giovanna Scapin 3,  Thierry Fischmann 3,  Asra Mirza 4,  Priya Dayananth 5,  Ronald E Painter 5,  Artjohn Villafania 5,  Charles G Garlisi 5,  Rumin Zhang 5,  Todd W Mayhood 5,  Qian Si 5,  Nianyu Li 6,  Rupesh P Amin 6,  Feifei Chen 6,  Bhavana Bhatt 6,  Christopher P Regan 6,  Hilary Regan 6,  Xinjie Lin 7,  Jin Wu 7,  Andrew Leithead 8,  Katherine Young 4,  Alexander Pasternak 2
Affiliations

Affiliations

  • 1 Merck & Co., Inc., Department of Medicinal Chemistry, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: frank.bennett@merck.com.
  • 2 Merck & Co., Inc., Department of Medicinal Chemistry, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
  • 3 Merck & Co., Inc., Department of Computational and Structural Chemistry, 126 E. Lincoln Avenue., Rahway, NJ 07065, USA.
  • 4 Merck & Co., Inc., Department of Infectious Diseases, 770 Sumneytown Pike., West Point, PA 19486, USA.
  • 5 Merck & Co., Inc., Department of Pharmacology, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 6 Merck & Co., Inc., Department of Nonclinical Drug Safety, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 7 Merck & Co., Inc., Department of Pharmacokinetics and Pharmacodynamics, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 8 Merck & Co., Inc., Department of Pharmaceutical Sciences, 770 Sumneytown Pike, West Point, PA 19486, USA.
PMID: 39396683 DOI: 10.1016/j.bmcl.2024.129989
Abstract

The design, syntheses and Antibacterial evaluation of sulfone analogues of previously disclosed Metallo-β-lactamase inhibitors (MBLis) are described. The novel derivatives were overall more effective in gram-negative Bacterial cell-based assays when combined with imipenem and relebactam. The major contributors to the improved anti-bacterial activity are enhanced enzyme-inhibitor interactions and reduced Bacterial cell efflux monitored via an efflux assay involving isogenic Pseudomonas aeruginosa efflux + and efflux - tool strains.

Keywords

Anti-bacterial; Metallo-β-lactamase; Sulfone; β-lactamase.

Figures
Products