Impact of Conjugation of the Reactive Oxygen Species (ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial Peptoids: Promoting Multitarget Mechanism and Enhancing Selectivity,Journal of Medicinal Chemistry

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Impact of Conjugation of the Reactive Oxygen Species (ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial Peptoids: Promoting Multitarget Mechanism and Enhancing Selectivity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c00775
Dasom Song ₁ , Byeongkwon Kim ₂ , Minsang Kim ₁ , Jin Kyeong Lee ₂ , Jieun Choi ₁ , Hyeju Lee ₂ , Sujin Shin ₃ , Dongmin Shin ₁ , Ho Yeon Nam ₁ , Yunho Lee ₃ , Seongsoo Lee _{4,

5,

6} , Yangmee Kim ₂ , Jiwon Seo ₁

Affiliation

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.

中文翻译：

活性氧 (ROS) 生成催化部分与膜活性抗菌肽缀合的影响：促进多靶点机制并增强选择性

抗菌肽（AMP）代表了对抗多重耐药细菌感染的有前途的治疗方式。作为天然 AMP 的模拟物，拟肽寡聚物如类肽（即寡聚N取代甘氨酸）已被用于抗蛋白水解降解的抗菌剂。在这里，我们探索了催化金属结合基序——氨基末端 Cu(II) 和 Ni(II) 结合 (ATCUN) 基序——与阳离子两亲抗菌肽的缀合，以增强其功效。与 Cu(II) 或 Ni(II) 络合后，缀合物催化羟基自由基的产生，并且22和22-Cu 的选择性比亲本类肽提高了 10 倍以上，这可能是由于疏水性降低所致。 Cu-ATCUN-类肽引起细菌膜破坏、细胞内生物分子聚集、DNA 氧化和脂质过氧化，促进多种杀伤机制。在小鼠脓毒症模型中， 22表现出抗菌和抗炎功效且毒性低。这项研究提出了一种策略，通过整合 ROS 生成基序来提高膜作用抗菌肽的效力，从而增加氧化损伤作为杀伤机制。

更新日期：2024-08-29

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