Impact of Conjugation\nof the Reactive Oxygen Species\n(ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial\nPeptoids: Promoting Multitarget Mechanism and Enhancing Selectivity

Antimicrobial peptides (AMPs) represent promising therapeutic\nmodalities\nagainst multidrug-resistant bacterial infections. As a mimic of natural\nAMPs, peptidomimetic oligomers like peptoids (i.e., oligo-<i>N</i>-substituted glycines) have been utilized for antimicrobials\nwith resistance against proteolytic degradation. Here, we explore\nthe conjugation of catalytic metal-binding motifsthe amino\nterminal Cu(II) and Ni(II) binding (ATCUN) motifwith cationic\namphipathic antimicrobial peptoids to enhance their efficacy. Upon\ncomplexation with Cu(II) or Ni(II), the conjugates catalyzed hydroxyl\nradical generation, and <b>22</b> and <b>22-Cu</b> exhibited\nover 10-fold improved selectivity compared to the parent peptoid,\nlikely due to reduced hydrophobicity. Cu-ATCUN-peptoids caused bacterial\nmembrane disruption, aggregation of intracellular biomolecules, DNA\noxidation, and lipid peroxidation, promoting multiple killing mechanisms.\nIn a mouse sepsis model, <b>22</b> demonstrated antimicrobial\nand anti-inflammatory efficacy with low toxicity. This study suggests\na strategy to improve the potency of membrane-acting antimicrobial\npeptoids by incorporating ROS-generating motifs, thereby adding oxidative\ndamage as a killing mechanism.