Design, Synthesis, and Biological Evaluation of Membrane-Active Bakuchiol Derivatives as Effective Broad-Spectrum Antibacterial Agents

Infections caused by drug-resistant
bacteria seriously endanger
human health and global public health. Therefore, it is urgent to
discover and develop novel antimicrobial agents to combat multidrug-resistant
bacteria. In this study, we designed and synthesized a series of new
membrane-active bakuchiol derivatives by biomimicking the structure
and function of cationic antibacterial peptides. The most promising
compound 28 displayed potent antibacterial activity against
both Gram-positive bacteria (minimum inhibitory concentration, MIC
= 1.56–3.125 μg/mL) and Gram-negative bacteria (MIC =
3.125 μg/mL), very weak hemolytic activity, and low cytotoxicity.
Compound 28 had rapid bactericidal properties and avoided
bacterial resistance. More importantly, compound 28 showed
strong in vivo antibacterial efficacy against Staphylococcus aureus and Pseudomonas
aeruginosa in murine corneal infection models. This
design strategy is expected to provide an effective solution to the
antibiotic crisis.