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 Staphylococcus aureus (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 8j, which exhibited low hemolytic toxicity and the best selectivity against S. aureus (SI > 2000), showed good activity against clinical MRSA isolates (MIC = 0.5–2 μg/mL). Compound 8j was able to quickly kill bacteria without inducing bacterial resistance. A mechanistic study and transcriptome analysis revealed that compound 8j can act on phosphatidylglycerol and induce the accumulation of endogenous reactive oxygen species, which can destroy bacterial membranes. Importantly, compound 8j 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 8j had the potential to be an antibacterial agent against MRSA.