Discovery of di-amino acid antimicrobial peptide mimetics with heteroatom-incorporated linkers for potent antibacterial activity and low hemolytic toxicity.

The rise of multidrug-resistant bacterial infections severely endangers human health. Herein, we prepared two classes of di-amino acid antimicrobial peptide mimetics bearing either simple alkyl chains or heteroatom-incorporated alkyl chains as linkers. The mimetics bearing simple alkyl chains as linkers all exhibited high hemolytic toxicity, whereas the compounds with heteroatom-containing alkyl chains as linkers displayed both potent antibacterial activity and low hemolytic toxicity. Among them, 7d exhibited potent antibacterial effects against S. aureus and MRSA (MIC = 0.5-1 μg/mL), along with low hemolytic toxicity. Moreover, 7d was characterized by rapid bactericidal kinetics and a low potential for resistance emergence. Furthermore, 7d both prevented S. aureus biofilm formation and disrupted established biofilms. Mechanistic and transcriptomic analyses indicated that 7d kills bacteria by disrupting the cell membrane, causing ROS accumulation and metabolic disturbances. Importantly, 7d showed strong in vivo antibacterial activity in a mouse subcutaneous infection model. Collectively, these results suggest that 7d is a promising lead compound for treating bacterial infections.