Light-Activated Silver Nanoparticles to Eliminate Antibiotic Resistant Bacteria and Genes

光激活银纳米颗粒消除抗生素耐药细菌和基因

• 批准号: 10670062
• 负责人: Juan Luis Vivero-Escoto
• 金额: $ 14.69万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670062
• 关键词: Aerobic; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Area; Award; Bacteria; Bacterial Antibiotic Resistance; Biological; Cell Death; Cells; Chemicals; Chemistry; DNA; Data; Development; Dyes; Environment; Environmental Engineering technology; Evaluation; Formulation; Friends; Generations; Genes; Goals; Grant; Horizontal Gene Transfer; Ions; Kinetics; Light; Mammalian Cell; Membrane; Metabolic Pathway; Minimum Inhibitory Concentration measurement; Modality; Mutation; Outcomes Research; Pathway interactions; Persons; Photosensitizing Agents; Production; Property; Public Health; Pump; Reactive Oxygen Species; Reporting; Research; Resistance; Resistance development; Silver; Students; Surface; Surface Properties; System; Technology; Testing; Therapeutic; Therapeutic Effect; Training; Translating; Translations; Visible Radiation; antibiotic resistant infections; antimicrobial; antimicrobial drug; bacterial resistance; career; cytotoxic; cytotoxicity; daughter cell; design; effective therapy; efflux pump; extracellular; graduate student; innovation; irradiation; microbial; nanomaterials; nanoparticle; nanoparticulate; nanotechnology platform; novel; oxidation; pathogen; protoporphyrin IX; rational design; resistance gene; resistance mechanism; success; undergraduate student

Abstract The development of microbial resistance to antimicrobial agents is one of the biggest public health issues of the 21st century. Antibiotic-resistant bacteria (ARB) cause more than 2.8 million antibiotic-resistant infections in the U.S. each year, and more than 35,000 people die as a result. The principal ways of antibiotic resistance development are related to the intrinsic bacteria’s ability to evolve rapidly through mutations to either modify these targets or the pathways for their synthesis, alter or degrade the antibiotic, or pump the antibiotic out of the cell. Moreover, of critical importance is that all of these resistance mechanisms are encoded by antibiotic resistance genes (ARGs), which are stable molecules encoded in the DNA and can be passed to daughter cells or transported by horizontal gene transfer to neighboring pathogens. Despite tremendous efforts utilizing a wide range of antibiotic discovery platform strategies, their success has been at best incremental. Therefore, there is a critical need to develop effective approaches to simultaneously eliminate both ARB and ARGs. Recently, the use of nanomaterials with antimicrobial activity has been explored as a new alternative against ARB and ARGs. Silver nanoparticles (AgNPs) have been reported to have myriad applications as antimicrobial agents. In addition, photodynamic inactivation (PDI) is also a feasible strategy to eliminate ARB and ARGs. The remarkable features of AgNPs such as large surface area, capability to carry and release Ag+ ions, and ability to modulate the microbial influx/efflux pumps; and PDI like efficient generation of ROS and the fact that does not generate further resistance make these treatment modalities a promising alternative for the inactivation of ARB and ARGs. We hypothesize that by combining both approaches, PDI and AgNPs, in the same platform a synergistic effect to eliminate ARB and destroy ARGs will be achieved. The main goal of this project is to develop a light-activated silver nanoparticulate system for the effective treatment of ARB and ARGs. This project consists of three aims: in Aim 1, we will synthesize and characterize protoporphyrin IX (PpIX)-loaded AgNPs. This aim will demonstrate that fabricating a rationally designed AgNP platform will enable a large payload of PpIX to be carried in a stable formulation with tunable surface properties. For Aim 2, we will investigate the chemical and colloidal stability of PpIX-AgNP materials under different culture medium and light irradiation conditions. This aim will provide key information for the optimization of the platform and the influence of the environment on the generation of ROS and Ag+ ions. Finally, in Aim 3, we will study the antimicrobial efficacy of PpIX-AgNPs against a panel of ARB, the ARGs degradation kinetics and the nanoparticles cytotoxicity in mammalian cells. The information obtained in this aim will allow us to move forward this platform to therapeutic applications.

抽象的 微生物对抗菌剂的耐药性的发展是最大的公共卫生问题之一 21世纪。抗生素耐药菌（ARB）在该抗生素中引起超过280万抗生素的感染 每年美国，结果有35,000多人死亡。抗生素抗性的主要方法 开发与内在细菌通过突变迅速发展以修改的能力有关 这些靶标的或它们合成，改变或降解抗生素的途径，或将抗生素从中泵出 细胞。而且，至关重要的是，所有这些抗性机制均由抗生素编码 抗性基因（ARGS），它是编码在DNA中的稳定分子，可以传递给子细胞 或通过水平基因转移到相邻病原体中运输。尽管巨大的努力使用了 抗生素发现平台策略范围，其成功充其量是增量。因此，有 开发有效方法同时消除ARB和ARGS的迫切需要。最近， 使用具有抗菌活性的纳米材料作为针对ARB和ARGS的新替代方法。 据报道，银纳米颗粒（AGNP）作为抗菌剂的应用多种。在 此外，光动力失活（PDI）也是消除ARB和ARGS的可行策略。杰出的 AGNP的特征，例如大的表面积，携带和释放Ag+离子的能力以及调节能力 微生物影响/外排泵；和PDI，例如有效的ROS产生，而没有产生的事实 进一步的抵抗使这些治疗方式成为灭活ARB和ARGS的有希望的替代方法。 我们假设通过将这两种方法（PDI和AGNP）结合在同一平台中 消除ARB和销毁将实现。该项目的主要目标是开发光激活 银纳米标志系统，可有效治疗ARB和ARGS。该项目由三个目标组成： 在AIM 1中，我们将综合并表征postondphyrin IX（PPIX）加载的AGNP。这个目标将证明 制造合理设计的AGNP平台将使大量的PPIX能够在稳定的 对于AIM 2，我们将研究 在不同培养基和光照射条件下的PPIX-AGNP材料。这个目标将提供关键 优化平台的信息以及环境对ROS产生的影响 和Ag+离子。最后，在AIM 3中，我们将研究PPIX-AGNPS对ARB面板的抗菌效率， 哺乳动物细胞中的ARGS降解动力学和纳米颗粒细胞毒性。获得的信息 在此目标中，我们可以将此平台推向治疗应用。