Development of biaromatic core-linked antimicrobial peptide mimics: Substituent position significantly affects antibacterial activity and hemolytic toxicity

Abstract

The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 μg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 μg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.