Exploration of membrane-active cephalosporin derivatives as potent antibacterial agents against Staphylococcus aureus biofilms and persisters

Developing innovative antimicrobial agents is essential in the fight against drug-resistant bacteria, as well as biofilms and persistent bacteria. In this study, four series of amphiphilic cephalosporin derivatives were synthesized. Most of the compounds showed good activity against Gram-positive bacteria, among which membrane-active cephalosporin 15e showed high activity against Staphylococcus aureus. Furthermore, 15e can maintain antimicrobial activity in mammalian body fluids and does not develop detectable resistance. Antibacterial mechanism studies demonstrated that the compound 15e can destroy the bacterial cell membrane, causing leakage of intracellular nucleic acids and proteins. Moreover, it can also suppress bacterial metabolic activity and induce the accumulation of reactive oxygen species (ROS) in the bacteria. Of greater significance, compound 15e effectively prevented the formation of biofilms and eradicated established biofilms and persister cells. Notably, compound 15e exhibited potent in vivo antibacterial efficacy, which was better than cephalothin. These findings suggest that 15e has a potential to become a drug candidate for treating bacterial infections.