湖南大学冯欣欣团队报道了一种全局破坏病原菌无耐药性致死性的策略——配体-受体相互作用诱导的细胞内相分离。相关研究成果发表在2024年7月9日出版的《美国化学会志》。

应对细菌耐药性的全球挑战需要创新的方法，其中多目标是一种广泛使用的策略。目前的多靶向策略，通常通过药物组合或单一药物固有地针对多个靶点来实现，面临着严格的药代动力学和药效学要求以及细胞毒性问题等挑战。

该文中，研究人员提出了一种细菌特异性全局破坏方法，作为一种广泛扩展的多目标策略，可以有效地破坏细菌亚细胞组织。这种效果是通过配体-受体相互作用诱导的小分子聚集的开创性化学设计实现的，即DNA诱导的二芳基肽模拟物在细菌细胞内的聚集。这些细胞内聚集体表现出对各种蛋白质的亲和力，从而显著干扰细菌的基本功能，并以“由内而外”的方式破坏细菌细胞膜，从而产生强大的抗菌活性和抑制耐药性。

此外，对大分子结合亲和力、细胞质定位模式和细菌应激反应的生化分析表明，这种细菌特异性细胞内聚集机制与非选择性经典DNA或膜结合机制有根本不同。这些机制上的区别，加上拟肽对细菌膜的选择性渗透，有助于其良好的生物相容性和药代动力学特性，使其能够在几种动物模型中发挥体内抗菌功效，包括基于小鼠的浅表伤口模型、皮下脓肿模型和败血症感染模型。

这些结果突出了配体-受体相互作用诱导的细胞内聚集，在实现全局破坏性多靶向效应方面的巨大前景，从而在治疗恶性细胞（包括病原体、肿瘤细胞和感染组织）方面提供了潜在应用。

附：英文原文

Title: Ligand–Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria

Author: Anming Yang, Junfeng Song, Jiaqi Li, Youzhi Li, Silei Bai, Cailing Zhou, Min Wang, Yu Zhou, Kang Wen, Miaomiao Luo, Peiren Chen, Bo Liu, Huan Yang, Yugang Bai, Wing-Leung Wong, Qingyun Cai, Huangsheng Pu, Yu Qian, Wenhao Hu, Wei Huang, Muyang Wan, Chunhui Zhang, Xinxin Feng

Issue&Volume: July 9, 2024

Abstract: Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand–receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an “inside-out” manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic’s selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand–receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues.

DOI: 10.1021/jacs.4c04749

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c04749