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

[Display omitted] •Gram-Negative Bacterial Coverage.•Anti-bacterial Resistance.•Sulfone Containing Drug.•Histamine Release.•Enzyme-Inhibitor X- Ray Co-Structure. 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.