Impact of Conjugation of the Reactive Oxygen Species (ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial Peptoids: Promoting Multitarget Mechanism and Enhancing Selectivity
Dasom Song, Byeongkwon Kim, Minsang Kim, Jin Kyeong Lee, Jieun Choi, Hyeju Lee, Sujin Shin, Dong Min Shin, Ho Yeon Nam, Yunho Lee, Seongsoo Lee, Yangmee Kim, Jiwon Seo
Abstract
Antimicrobial peptides (AMPs) represent promising therapeutic modalities against multidrug-resistant bacterial infections. As a mimic of natural AMPs, peptidomimetic oligomers like peptoids (i.e., oligo- N -substituted glycines) have been utilized for antimicrobials with resistance against proteolytic degradation. Here, we explore the conjugation of catalytic metal-binding motifs─the amino terminal Cu(II) and Ni(II) binding (ATCUN) motif─with cationic amphipathic antimicrobial peptoids to enhance their efficacy. Upon complexation with Cu(II) or Ni(II), the conjugates catalyzed hydroxyl radical generation, and 22 and 22-Cu exhibited over 10-fold improved selectivity compared to the parent peptoid, likely due to reduced hydrophobicity. Cu-ATCUN-peptoids caused bacterial membrane disruption, aggregation of intracellular biomolecules, DNA oxidation, and lipid peroxidation, promoting multiple killing mechanisms. In a mouse sepsis model, 22 demonstrated antimicrobial and anti-inflammatory efficacy with low toxicity. This study suggests a strategy to improve the potency of membrane-acting antimicrobial peptoids by incorporating ROS-generating motifs, thereby adding oxidative damage as a killing mechanism.