Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis
Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis
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吞噬体铜促进细胞内结核分枝杆菌的氧化攻击
DOI：
10.1021/acsinfecdis.8b00171
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发表时间：
2018
影响因子：
5.3
通讯作者：
Barczak, Amy
中科院分区：
文献类型：
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作者：
Libardo, M. Daben;de la Fuente-Nuñez, Cesar;Anand, Kushi;Krishnamoorthy, Gopinath;Kaiser, Peggy;Pringle, Stephanie C.;Dietz, Christopher;Pierce, Scott;Smith, Michael B.;Barczak, Amy
铜（Cu）离子在控制细菌感染中是至关重要的，并且成功的病原体如结核分枝杆菌（Mtb）具有多种Cu抗性机制。我们报告，作为概念的证明，一种新的铜过敏表型可以产生在分枝杆菌，包括结核分枝杆菌，通过肽，DAB-10，能够形成活性氧（ROS）后，铜结合。DAB-10在体外和感染过程中以铜依赖的方式诱导分枝杆菌内氧化应激。DAB-10穿透小鼠巨噬细胞并遇到细胞内的分支杆菌。当用DAB-10与细胞可渗透的Cu螯合剂一起处理Mtb感染的巨噬细胞时，观察到显著的细胞内Cu依赖性保护。用Cu螯合剂处理逆转了由DAB-10诱导的分枝杆菌内氧化转变。我们得出结论，DAB-10利用宿主-结核分枝杆菌界面中的吞噬体Cu离子池来增强巨噬细胞的杀分枝杆菌活性，同时利用结核分枝杆菌对ROS的敏感性。DAB-10可作为开发下一代多功能抗菌剂的模型。
Copper (Cu) ions are critical in controlling bacterial infections, and successful pathogens likeMycobacterium tuberculosis(Mtb) possess multiple Cu resistance mechanisms. We report, as proof of concept, that a novel Cu hypersensitivity phenotype can be generated in mycobacteria, including Mtb, through a peptide, DAB-10, that is able to form reactive oxygen species (ROS) following Cu-binding. DAB-10 induces intramycobacterial oxidative stress in a Cu-dependent mannerin vitroand during infection. DAB-10 penetrates murine macrophages and encounters intracellular mycobacteria. Significant intracellular Cu-dependent protection was observed when Mtb-infected macrophages were treated with DAB-10 alongside a cell-permeable Cu chelator. Treatment with the Cu chelator reversed the intramycobacterial oxidative shift induced by DAB-10. We conclude that DAB-10 utilizes the pool of phagosomal Cu ions in the host–Mtb interface to augment the mycobactericidal activity of macrophages while simultaneously exploiting the susceptibility of Mtb to ROS. DAB-10 serves as a model with which to develop next-generation, multifunctional antimicrobials.