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 微生物对抗菌药物耐药性的发展是当今世界最大的公共卫生问题之一 21世纪。抗生素耐药性细菌 (ARB) 在全球造成超过 280 万例抗生素耐药性感染 美国每年有超过 35,000 人因此死亡。抗生素耐药性的主要途径 发育与内在细菌通过突变快速进化的能力有关 这些目标或其合成途径，改变或降解抗生素，或将抗生素从细胞中泵出 细胞。此外，至关重要的是所有这些耐药机制都是由抗生素编码的 抗性基因 (ARG)，是 DNA 中编码的稳定分子，可以传递给子细胞 或通过水平基因转移转运至邻近的病原体。尽管付出了巨大的努力，利用了广泛的 尽管抗生素发现平台策略多种多样，但它们的成功充其量只是渐进式的。因此，有 迫切需要开发有效的方法来同时消除 ARB 和 ARG。最近， 人们正在探索使用具有抗菌活性的纳米材料作为对抗 ARB 和 ARG 的新替代品。 据报道，银纳米颗粒（AgNP）作为抗菌剂具有多种应用。在 此外，光动力灭活（PDI）也是消除ARB和ARGs的可行策略。非凡的 AgNPs 具有比表面积大、携带和释放 Ag+ 离子的能力以及调节能力等特点 微生物流入/流出泵；和 PDI 一样，ROS 的高效生成和不生成的事实 进一步的耐药性使这些治疗方式成为 ARB 和 ARG 失活的有希望的替代方案。 我们假设，通过将 PDI 和 AgNPs 这两种方法结合在同一平台上，可以产生协同效应 消除ARB、摧毁ARG的目标将得以实现。该项目的主要目标是开发一种光激活的 用于有效治疗 ARB 和 ARG 的银纳米颗粒系统。该项目包含三个目标： 在目标 1 中，我们将合成并表征负载原卟啉 IX (PpIX) 的 AgNP。这一目标将证明 构建合理设计的 AgNP 平台将使 PpIX 的大有效载荷能够稳定地承载 具有可调表面特性的配方。对于目标 2，我们将研究化学和胶体稳定性 不同培养基和光照条件下的PpIX-AgNP材料。这一目标将提供关键 平台优化以及环境对ROS生成影响的信息 和Ag+离子。最后，在目标 3 中，我们将研究 PpIX-AgNPs 对一组 ARB 的抗菌功效， ARGs 降解动力学和纳米颗粒在哺乳动物细胞中的细胞毒性。获得的信息 为了这个目标，我们将把这个平台推向治疗应用。