Discovery of adamantane-containing small-molecule peptidomimetics with membrane-disrupting activity for combating drug-resistant Bacteria

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-09-13 DOI:10.1016/j.bioorg.2025.108990

Jie Su , Yuhang He , Min Li , Zhiqiang Shen , Qingxian Ji , Yixuan Ren , Muhammad Subaan Fareed , Kairong Wang

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Abstract

The rising incidence of drug-resistant bacterial infections poses a significant threat to human health and highlights the urgent need for novel antimicrobial agents. In the present study, inspired by cationic antimicrobial peptides (AMPs) we developed a series of amphiphilic small-molecule peptidomimetics by incorporating adamantane as the hydrophobic moiety and alkylamines as hydrophilic moiety into the scaffold of natural amino acids to combat drug-resistant bacteria. Among them, the optimized compound A13 exhibited broad spectrum antimicrobial activity, especially against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus gallinarum, while maintaining high cell compatibility. A13 rapidly killed bacteria primarily through membrane disruption, a mechanism that reduces the likelihood of resistance development. Additionally, A13 demonstrated significant anti-biofilm activity, excellent stability, and effective in vivo therapeutic efficacy in mouse models of MRSA-induced keratitis and pneumonia. Therefore, this study holds promise in providing effective antimicrobial agents or new strategies for the discovery of novel antibiotics to treat drug-resistant bacterial infections.

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具有抗耐药细菌膜破坏活性的含金刚烷小分子拟肽物的发现

耐药细菌感染发病率的上升对人类健康构成了重大威胁，并突出了对新型抗菌药物的迫切需要。在本研究中，受阳离子抗菌肽（AMPs）的启发，我们开发了一系列两亲性小分子拟肽，将金刚烷作为疏水片段，烷基胺作为亲水片段加入天然氨基酸支架中，以对抗耐药细菌。其中，优化后的化合物A13具有广谱抗菌活性，特别是对多种革兰氏阳性菌，包括耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素鸡肠球菌，同时保持较高的细胞相容性。A13主要通过破坏膜迅速杀死细菌，这一机制降低了产生耐药性的可能性。此外，A13在mrsa诱导的角膜炎和肺炎小鼠模型中显示出显著的抗生物膜活性，良好的稳定性和有效的体内治疗效果。因此，本研究有望为发现治疗耐药细菌感染的新型抗生素提供有效的抗菌药物或新策略。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.