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唤醒生物膜以增强镓的自杀性摄取,用于慢性肺部感染的治疗。

Wake biofilm up to enhance suicidal uptake of gallium for chronic lung infection treatment.

机构信息

Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.

Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.

出版信息

Biomaterials. 2024 Oct;310:122619. doi: 10.1016/j.biomaterials.2024.122619. Epub 2024 May 17.

Abstract

The hypometabolic and nutrient-limiting condition of dormant bacteria inside biofilms reduces their susceptibility to antibacterial agents, making the treatment of biofilm-dominating chronic infections difficult. Herein, we demonstrate an intratracheal aerosolized maltohexaose-modified catalase-gallium integrated nanosystem that can 'wake up' dormant Pseudomonas aeruginosa biofilm to increase the metabolism and nutritional iron demand by reconciling the oxygen gradient. The activated bacteria then enhance suicidal gallium uptake since gallium acts as a 'Trojan horse' to mimic iron. The internalized gallium ions disrupt biofilms by interfering with the physiological processes of iron ion acquisition and utilization, biofilm formation, and quorum sensing. Furthermore, aerosol microsprayer administration and bacteria-specific maltohexaose modification enable accumulation at biofilm-infected lung and targeted release of gallium into bacteria to improve the therapeutic effect. This work provides a potential strategy for treating infection by reversing the dormant biofilm's resistance condition.

摘要

生物膜内休眠细菌的代谢减缓和营养限制条件降低了它们对抗菌药物的敏感性,使得治疗以生物膜为主导的慢性感染变得困难。在此,我们展示了一种经气管气溶胶化的麦芽六糖修饰的过氧化氢酶-镓整合纳米系统,该系统可以通过调节氧气梯度来“唤醒”休眠的铜绿假单胞菌生物膜,增加其代谢和营养铁需求。然后,由于镓可以作为“特洛伊木马”模拟铁,激活的细菌会增强自杀性镓摄取。镓离子通过干扰铁离子获取和利用、生物膜形成和群体感应等生理过程来破坏生物膜。此外,气溶胶微喷雾器给药和细菌特异性麦芽六糖修饰使药物在感染生物膜的肺部积累,并将镓靶向释放到细菌中,从而提高治疗效果。这项工作提供了一种通过逆转休眠生物膜的耐药状态来治疗感染的潜在策略。

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