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

Bioorg Med Chem Lett. 2024 Dec 1:114:129989. doi: 10.1016/j.bmcl.2024.129989. Epub 2024 Oct 11.

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.

MeSH terms

  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Drug Discovery
  • Gram-Negative Bacteria / drug effects
  • Microbial Sensitivity Tests*
  • Molecular Structure
  • Pseudomonas aeruginosa* / drug effects
  • Structure-Activity Relationship
  • Sulfones* / chemical synthesis
  • Sulfones* / chemistry
  • Sulfones* / pharmacology
  • beta-Lactamase Inhibitors* / chemical synthesis
  • beta-Lactamase Inhibitors* / chemistry
  • beta-Lactamase Inhibitors* / pharmacology
  • beta-Lactamases / metabolism

Substances

  • beta-Lactamase Inhibitors
  • Sulfones
  • Anti-Bacterial Agents
  • beta-Lactamases