Most naturally occurring and synthetically designed AMPs have been found to exert their antimicrobial activity via membrane disruption. Therefore, for macrocyclic peptides, in addition to key physicochemical properties such as net cationic charge, hydrophobic bulk, ring size, and backbone flexibility, the special orientation of the side chain could play a crucial role in selective and effective membrane interaction properties of macrocyclic peptides towards target microbial membranes.