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.

项目总结 由于抗菌素耐药性(AMR)的增加和 新抗生素研发停滞不前。如果不加以控制，每年可归因于AMR的死亡人数为 据估计，到2050年，这一数字将达到1000万，超过癌症和糖尿病的死亡人数。因此，有一个紧急的 需要开发创新的方法来应对这场严重的全球危机。我们的目标是开发一种新的 双刺激响应型多糖包被纳米粒(NP)可广泛包埋 FDA批准的抗生素可有效治疗多药耐药(MDR)细菌感染。多糖类 NP外壳确保良好的稳定性和长时间的血液循环，从而导致NP在体内的高积聚 通过增强渗透和滞留作用感染组织。此外，多糖能够使NP 由于对细菌凝集素的多价亲和力而物理结合病原体。唯一设计的NP是 在炎症微环境中被高水平的ROS和/或低pH激活以释放阳离子 抗菌聚合物和抗生素在对抗MDR病原体方面表现出很强的协同作用。阳离子 聚合物可以在细菌细胞膜上诱导毛孔，并显著降低细菌的内在抵抗力 通过加强抗生素向细菌的运输并允许它们绕过外排而感染病原体 打气筒。在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 微环境包裹了高水平的抗菌物质，从而导致了高抗菌效果。 此外，NP还可以穿透细菌生物膜，并通过宏观调控增强抗生素的摄取。 噬菌体，从而有效地消除了臭名昭著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，这些键很容易在 哺乳动物细胞的胞浆，从而避免了与其他阳离子的剂量限制毒性的问题 聚合物。在我们成功的初步研究之后，我们将系统地优化和表征定制的NP 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NPs的抗菌活性 并对抗生物被膜的疗效、耐药发展概况、生物相容性等方面进行了初步研究 了解针对感兴趣的病原体的有效和安全的抗微生物NP的设计规则。在AIM 3、我们将在体内确定最大耐受量、全身毒性、免疫后果 所选纳米粒在健康小鼠体内的生物分布、药代动力学和抗菌效果 临床相关的动物感染模型。总而言之，这项研究将导致一类新的抗菌纳米粒 基于疾病特异性刺激，一种独特的双刺激响应性和生物相容性阳离子聚合物WE 针对多药耐药病原体和FDA批准的抗生素的经过改造的多糖。如果成功，它将提供 有效消除最流行的MDR病原体的通用、有效和安全的解决方案。