Biomaterial‐Interrelated Bacterial Sweeper: Simplified Self‐Assembled Octapeptides with Double‐Layered Trp Zipper Induces Membrane Destabilization and Bacterial Apoptosis‐Like Death

Treatment of microbial-associated infections continues to be hampered by impaired antibacterial efficiency and the variability in nanomedicines. Herein, an octapeptide library with a double-layered zipper, constructed via a systematic arrangement, simplifying the sequence and optimizing the structure (diverse motifs including surfactant-like, central-bola, and end-bola), is assessed in terms of biological efficiency and self-assembly properties. The results indicate that peptides with double-layered Trp zipper exhibit significant antimicrobial activity. Extracellularly, affinity interactions between micelles and bacteria induce the lateral flow of the membrane and electric potential perturbation. Intracellularly, lead molecules cause apoptosis-like death, as indicated by excessive accumulation of reactive oxygen species, generation of a DNA ladder, and upregulation of mazEF expression. Among them, RW-1 performs the best in vivo and in vitro. The intersecting combination of Trp zipper and surfactants possesses overwhelming superiority with respect to bacterial sweepers (therapeutic index [TI] = 52.89), nanostructures (micelles), and bacterial damage compared to RW-2 (central-bola) and RW-3 (end-bola). These findings confirm that the combination of double-layered Trp zipper and surfactants has potential for application as a combined motif for combating microbial infection and connects the vast gap between antimicrobial peptides and self-assembly, such as Jacob's ladder.