GIST Scholar
College of Engineering
Department of Environment and Energy Engineering
1. Journal Articles
Impact of Conjugation of the Reactive Oxygen Species (ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial Peptoids: Promoting Multitarget Mechanism and Enhancing Selectivity
- Type
- Article
- Citation
- Journal of Medicinal Chemistry, v.67, no.17, pp.15148 - 15167
- Issued Date
- 2024-08
- 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. © 2024 American Chemical Society.
- Publisher
- American Chemical Society
- ISSN
- 0022-2623
- Appears in Collections:
- Department of Chemistry > 1. Journal Articles
Department of Environment and Energy Engineering > 1. Journal Articles
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