CPF-C1 analog with effective antimicrobial and antibiofilm activities against Staphylococcus aureus including MRSA

The evolution of Staphylococcus aureus (S. aureus) with the ability to acquire and develop resistance to antibiotics has been described as a distinct strain emergence event. Methicillin-resistant S. aureus (MRSA) is responsible for most global S. aureus bacteremia cases. Bacterial biofilms are one of the primary reasons for drug resistance. Biofilms formed by S. aureus are the most common cause of biofilm-associated infections, which increase the difficulty of treatment. Antimicrobial peptides (AMPs) represent promising candidates for the future treatment of antibiotic-resistant bacterial and biofilm-associated infections. In this study, we designed and synthesized a series of analogs to increase the druggability of the natural antimicrobial peptide CPF-C1. Among the analogs, CPF-2 showed high antimicrobial activity against MRSA and multidrug-resistant S. aureus isolated from clinics. In the serum and physiological salt environment, CPF-2 also exhibited effective antimicrobial activity. Importantly, CPF-2 did not determine resistance and showed no hemolytic activity at the active concentration. Concerning the mechanism of action, CPF-2 produced a rapid bactericidal effect by interrupting the bacterial membranes. Even more surprisingly, CPF-2 showed an excellent ability to prevent and eradicate biofilms caused by S. aureus and MRSA not only in vitro but also in vivo. Our results suggested that CPF-2 has potential as a lead compound to treat infections caused by S. aureus and MRSA, including the associated biofilms.