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Upon encountering bacterial membranes, strong PG recognition triggers a side-chain rearrangement, reorienting the cationic groups toward the membrane surface and exposing hydrophobic motifs for progressive bilayer insertion and disruption. Supportingly, lengthening the exposed terminal hydrophobic group increased interactions with proteins and mammalian lipids, reduced PG selectivity, and compromised antibiofilm efficacy, underscoring the importance of hidden hydrophobic domains for biofilm bacteria targeting. paRAP showed potent antibiofilm efficacy in vitro and in murine models of both periodontitis and urinary tract infections. 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