Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
J Med Chem. 2024 Sep 12;67(17):15148-15167. doi: 10.1021/acs.jmedchem.4c00775. Epub 2024 Aug 29.
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--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 and 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, 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.
抗菌肽 (AMPs) 是一种有前途的治疗多药耐药细菌感染的方法。作为天然 AMP 的模拟物，肽模拟物低聚物（例如，寡取代甘氨酸）已被用于具有抗蛋白水解降解能力的抗菌剂。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——与阳离子两亲性抗菌肽模拟物的缀合，以增强其功效。与 Cu(II) 或 Ni(II) 络合后，这些缀合物催化了羟基自由基的生成，并且与母体肽模拟物相比， 表现出超过 10 倍的选择性提高，这可能是由于疏水性降低所致。Cu-ATCUN-肽模拟物导致细菌膜破裂、细胞内生物分子聚集、DNA 氧化和脂质过氧化，促进了多种杀伤机制。在小鼠败血症模型中， 表现出抗菌和抗炎功效，且毒性低。这项研究提出了一种通过引入产生 ROS 的基序来提高膜作用抗菌肽模拟物效力的策略，从而增加氧化损伤作为一种杀伤机制。
