Self-Assembling\nand Pore-Forming Peptoids as Antimicrobial\nBiomaterials

Bacterial infections have been a serious threat to mankind\nthroughout\nhistory. Natural antimicrobial peptides (AMPs) and their membrane\ndisruption mechanism have generated immense interest in the design\nand development of synthetic mimetics that could overcome the intrinsic\ndrawbacks of AMPs, such as their susceptibility to proteolytic degradation\nand low bioavailability. Herein, by exploiting the self-assembly and\npore-forming capabilities of sequence-defined peptoids, we discovered\na family of low-molecular weight peptoid antibiotics that exhibit\nexcellent broad-spectrum activity and high selectivity toward a panel\nof clinically significant Gram-positive and Gram-negative bacterial\nstrains, including vancomycin-resistant Enterococcus\nfaecalis (VREF), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Tuning\nthe peptoid side chain chemistry and structure enabled us to tune\nthe efficacy of antimicrobial activity. Mechanistic studies using\ntransmission electron microscopy (TEM), bacterial membrane depolarization\nand lysis, and time–kill kinetics assays along with molecular\ndynamics simulations reveal that these peptoids kill both Gram-positive\nand Gram-negative bacteria through a membrane disruption mechanism.\nThese robust and biocompatible peptoid-based antibiotics can provide\na valuable tool for combating emerging drug resistance.