Antimicrobial resistance can be fought be developing new antibiotics inspired by Nature. The lantibiotic nisin is a valuable target given its potency, despite regular use in agriculture and food technology. Nisin is a polycyclic peptide which forms membrane nanopores, yet the molecular reason for its polycyclic nature remains unknown. Here we show that cyclisation is key to lower the entropic barrier for peptide membrane insertion. We derive the insight by synthesising Nisin analogues with partially linearised peptide stretches and characterising them with single-channel current recordings, microbiological assays, and molecular simulations. The prominent role of cyclical regions can guide the design of novel membrane-porating antimicrobial peptides.