Dual-Stimuli Responsive Antibiotic-Loaded Nanoparticles: A New Strategy to Overcome Antimicrobial Resistance

双刺激响应抗生素负载纳米颗粒：克服抗生素耐药性的新策略

• 批准号: 10703696
• 负责人: SHAOQIN GONG
• 金额: $ 49.06万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703696
• 关键词: Acinetobacter baumannii; Affinity; Animal Model; Animals; Antibiotics; Antimicrobial Resistance; Artificial nanoparticles; Bacteria; Bacterial Infections; Binding; Biodistribution; Blood Circulation Time; Bypass; Catheters; Cell membrane; Cessation of life; Chemicals; Clinical; Communicable Diseases; Cytosol; Development; Diabetes Mellitus; Disease; Dose Limiting; Drug Kinetics; ESKAPE pathogens; Electrostatics; Encapsulated; Engineering; Ensure; Escherichia coli; Exhibits; FDA approved; Formulation; Glutathione; Goals; Immune response; Immunologics; In Vitro; Individual; Infection; Inflammatory; Lectin; Left; Lung infections; Macrophage; Malignant Neoplasms; Mammalian Cell; Maximum Tolerated Dose; Membrane; Microbe; Microbial Biofilms; Modeling; Modification; Multi-Drug Resistance; Mus; Penetration; Pharmaceutical Preparations; Pilot Projects; Polymers; Polysaccharides; Pseudomonas aeruginosa; Public Health; Rattus; Reactive Oxygen Species; Resistance; Shapes; Stimulus; Thigh structure; Tissues; Toxic effect; Treatment Efficacy; Venous; antimicrobial; attributable mortality; biomaterial compatibility; clinically relevant; combat; cost; design; drug resistance development; efflux pump; extracellular; human pathogen; in vivo; innovation; interest; methicillin resistant Staphylococcus aureus; multi-drug resistant pathogen; nanoparticle; novel antibiotic class; pathogen; synergism; systemic toxicity; uptake

PROJECT SUMMARY Infectious diseases are a growing threat to public health owing to increasing antimicrobial resistance (AMR) and stagnation in new antibiotic development. Left unchecked, the annual number of deaths attributable to AMR is estimated to reach 10 million by 2050, exceeding deaths due to cancers and diabetes. Thus, there is an urgent need to develop innovative approaches to tackle this serious global crisis. We aim to develop a new class of dual-stimuli responsive polysaccharide-coated nanoparticles (NP) capable of encapsulating a wide range of FDA-approved antibiotics to effectively treat multidrug-resistant (MDR) bacterial infections. The polysaccharide NP shell ensures good stability and long blood circulation time, thus leading to high NP accumulation in the infected tissues via the enhanced permeation and retention effect. Furthermore, polysaccharides enable the NP to physically bind the pathogens due to multivalent affinity for bacterial lectins. The uniquely engineered NP is activated by high levels of ROS and/or low pH in the inflammatory microenvironment to release both cationic antimicrobial polymers and antibiotics that show a strong synergy to combat MDR pathogens. The cationic polymers can induce pores on the bacterial cell membrane, and significantly diminish the intrinsic resistance of the pathogens by enhancing the transport of antibiotics into the bacteria and allowing them to bypass the efflux pump. The cationic polymers released in the infected tissues can also agglomerate the pathogens and shape a microenvironment entrapping a high level of antimicrobial materials, thus leading to high antimicrobial efficacy. Moreover, the NP can penetrate through bacterial biofilms, and enhance the uptake of antibiotics by macro- phages, thereby effectively eliminating notoriously challenging biofilm and intracellular infections, respectively. Finally, the cationic polymer contains GSH-cleavable bonds in its main chain, which can be readily degraded in the cytosol of mammalian cells, thereby sidestepping the problem of dose-limiting toxicity with other cationic polymers. Following on our successful pilot studies, we will systematically optimize and characterize NPs tailored to treat four different MDR pathogens. In Aim 1, we will determine the optimal polysaccharide NP shell, antibiotics, and NP formulation for each of the four MDR pathogens. In Aim 2, we will study the candidate NPs’ antimicrobial and antibiofilm efficacy, drug resistance development profile, and biocompatibility to gain a fundamental understanding of the design rules for efficacious and safe antimicrobial NP against pathogens of interest. In Aim 3, we will determine the maximum tolerated dose, systemic toxicity, immunological consequences, in vivo biodistribution, pharmacokinetics, and antimicrobial efficacy of the selected NPs in healthy mice and three clinically relevant animal infection models. Altogether, this study will lead to a new class of antimicrobial NPs based on disease-specific stimuli, a unique dual-stimuli responsive and biocompatible cationic polymer we engineered, polysaccharides targeting MDR pathogens, and FDA-approved antibiotics. If successful, it will offer a general, yet effective and safe solution to effectively eliminate the most prevalent MDR pathogens.

项目概要 传染病对公共卫生债务构成日益严重的威胁，因为抗生素耐药性（AMR）不断增加， 如果不加以控制，新抗生素的开发停滞不前，每年因抗菌素耐药性导致的死亡人数为 预计到 2050 年，这一数字将达到 1000 万人，超过癌症和糖尿病造成的死亡人数。 需要制定创新方法来应对这一严重的全球危机。 双刺激响应多糖涂层纳米颗粒（NP），能够封装多种 FDA 批准的抗生素可有效治疗多重耐药 (MDR) 细菌感染。 NP壳保证了良好的稳定性和较长的血液循环时间，从而导致NP在体内大量积累 通过增强的渗透和滞留效应，多糖能够使 NP 进入受感染的组织。 由于对细菌凝集素的多价亲和力，物理结合病原体。 被炎症微环境中高水平的 ROS 和/或低 pH 值激活，释放出阳离子 抗菌聚合物和抗生素在对抗 MDR 病原体方面表现出强大的协同作用。 聚合物可以在细菌细胞膜上诱导孔隙，并显着降低细菌的固有电阻 通过增强抗生素向细菌的转运并允许它们绕过外排来消灭病原体 受感染组织中释放的阳离子聚合物也可以聚集病原体并形成一个形状。 微环境捕获高水平的抗菌材料，从而产生高抗菌功效。 此外，纳米颗粒可以穿透细菌生物膜，增强宏观对抗生素的吸收。 噬菌体，从而有效地分别消除众所周知的具有挑战性的生物膜和细胞内感染。 最后，阳离子聚合物的主链中含有 GSH 可裂解的键，可以很容易地在环境中降解。 哺乳动物细胞的细胞质，从而避免了与其他阳离子的剂量限制毒性问题 继我们成功的试点研究之后，我们将系统地优化和表征定制的纳米颗粒。 治疗四种不同的 MDR 病原体 在目标 1 中，我们将确定最佳的多糖 NP 壳、抗生素、 以及针对四种 MDR 病原体的 NP 配方 在目标 2 中，我们将研究候选 NP 的抗菌作用。 和抗生物膜功效、耐药性发展概况和生物相容性，以获得基本的 了解针对目标病原体的有效且安全的抗菌纳米颗粒的设计规则。 3、我们将确定最大耐受剂量、全身毒性、免疫学后果、体内 所选纳米颗粒在健康小鼠和三种药物中的生物分布、药代动力学和抗菌功效 总而言之，这项研究将产生一类新的抗菌纳米颗粒。 基于疾病特异性刺激，我们开发了一种独特的双刺激响应和生物相容性阳离子聚合物 如果成功，它将提供针对 MDR 病原体的工程多糖和 FDA 批准的抗生素。 一种通用、有效且安全的解决方案，可有效消除最流行的耐多药病原体。