Development of Aromatic-Linked Diamino Acid Antimicrobial Peptide Mimics with Low Hemolytic Toxicity and Excellent Activity against Methicillin-Resistant Staphylococcus aureus (MRSA).

Infections caused by methicillin-resistant (MRSA) have become one of the biggest threats to public health. To develop new antibacterial agents against MRSA, a series of diamino acid compounds with aromatic nuclei linkers were designed and synthesized. Compound , which exhibited low hemolytic toxicity and the best selectivity against (SI > 2000), showed good activity against clinical MRSA isolates (MIC = 0.5-2 μg/mL). Compound was able to quickly kill bacteria without inducing bacterial resistance. A mechanistic study and transcriptome analysis revealed that compound can act on phosphatidylglycerol and induce the accumulation of endogenous reactive oxygen species, which can destroy bacterial membranes. Importantly, compound achieved a 2.75 log reduction of MRSA count at 10 mg/kg/d in a mouse subcutaneous infection model. These findings suggested that compound had the potential to be an antibacterial agent against MRSA.