Development of membrane-targeting chalcone derivatives as antibacterial agents against multidrug-resistant bacteria.

The striking rise of infections caused by multidrug-resistant pathogens has evolved as a serious threat to public health worldwide. To develop new antibacterials to combat multidrug-resistant bacteria, a novel class of amphiphilic chalcone derivatives serving as antimicrobial peptidomimetics was designed and synthesized. Among them, the most promising compound 14b displayed broad-spectrum antimicrobial activity against both Gram-positive bacteria (MICs = 0.5-1 μg/mL) and Gram-negative bacteria (MICs = 1-32 μg/mL), low hemolytic activity, and good membrane selectivity. Moreover, compound 14b exhibited rapid bactericidal action, a low probability of developing resistance, high proteolytic stability, and strong capabilities of inhibiting and destroying bacterial biofilms. Further mechanism investigations revealed that compound 14b possessed strong membrane-disrupting abilities and could disintegrate the integrity of bacterial cell membranes by destroying transmembrane potential and enhancing membrane permeability, and causing the generation of intracellular ROS and the leakage of DNA and proteins, ultimately leading to bacterial death. More importantly, compound 14b also showed excellent in vivo therapeutic potency in a mouse septicemia model infected by both Gram-positive and Gram-negative bacteria, indicating its potential to be an antibacterial agent to confront bacterial infections.