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Informed by our prior structure-activity work, we demonstrate that transposition of an N-terminal biphenyl motif from full-length LL-37 onto the previously-described central activity region (residues 18-29) improves activity against gram-negative bacteria by &gt;16-fold. We further improve upon this lead derivative, termed FF-14, using stabilizing modifications such as D-amino acids and C-terminal amidation as well as selected N-lipidation moieties, and demonstrate the transferability of biphenyl motif activity to longer cathelicidin scaffolds. Mechanistic interrogation reveals that the biphenyl pharmacophore increases both inner and outer membrane permeabilization while promoting helical structure in the 14-mer without directly impacting peptide stability. 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