Design, Synthesis, and Preliminary Investigation on the Mode of Action for a Series of Novel Antimicrobial Peptidomimetics

Abstract Over the years, many antibiotics have been developed, but most have become less effective due to antimicrobial resistance, especially those targeting enzymatic pathways. This growing resistance poses a serious global health threat. It is now recognized that physically disrupting bacterial cell membranes is less prone to resistance development. Antimicrobial peptides (AMPs) are promising in this regard, though their broader application is limited by their susceptibility to proteolytic degradation and toxicity. To address these issues, peptidomimetics have emerged as a new class of antibacterial agents. In this study, a library of AMPs were designed and synthesized, inspired by magainin, a defensin-mimetic molecule, and brilacidin. Modifying side chain lengths proved essential for effective insertion into phospholipid bilayers. A modular synthetic approach was developed, enabling the generation of diverse derivatives to explore structure−activity relationships. The compounds were tested against clinically relevant pathogens, showing promising antimicrobial activity, and preliminary studies confirmed a membranolytic mechanism of action.