Stimuli-Responsive Polymer-Drug Conjugates: A New Strategy to Fight Antimicrobial Resistance

刺激响应性聚合物药物偶联物：对抗抗菌素耐药性的新策略

• 批准号: 10415193
• 负责人: SHAOQIN GONG
• 金额: $ 22.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415193
• 关键词: Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Biodistribution; Bypass; Catheters; Cations; Cessation of life; Characteristics; Charge; Clinical; Communicable Diseases; Data; Development; Diabetes Mellitus; Disease; Drug resistance; Engineering; Ensure; Escherichia coli; Exhibits; FDA approved; Glutathione; Goals; Gram-Negative Bacteria; Implant; In Vitro; Infection; Inflammation; Inflammatory; Left; Malignant Neoplasms; Mammalian Cell; Maximum Tolerated Dose; Membrane; Microbial Biofilms; Modeling; Penetration; Peritonitis; Pharmaceutical Preparations; Polymers; Pseudomonas aeruginosa; Public Health; Pump; Reactive Oxygen Species; Resistance; Resistance development; Site; Staphylococcus aureus; Stimulus; Surface; Thigh structure; Tissues; Toxic effect; Treatment Efficacy; antimicrobial; attributable mortality; base; biomaterial compatibility; clinically relevant; combat; cost; design; dosage; efflux pump; fighting; human pathogen; improved; in vivo; innovation; methicillin resistant Staphylococcus aureus; mouse model; novel antibiotic class; pathogen; synergism; systemic toxicity

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 innovative, highly efficient, and biocompatible pH- or ROS-responsive antimicrobial polymer- drug (i.e., antibiotics) conjugates (PDCs), which can effectively treat serious infectious diseases and overcome AMR while ensuring high biocompatibility. We will accomplish this goal utilizing existing FDA-approved antibiotics, disease-specific stimuli, and a uniquely engineered biocompatible cationic polymer. Cationic polymers can be effective antibiotic carriers as they can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and allowing them to bypass the efflux pump in the bacterial membrane. Cationic PDCs can also (1) stick to the bacteria’s surface, thereby serving as a drug reservoir to release drug locally, and (2) effectively infiltrate bacterial biofilms, thereby leading to deeper antibiotic penetration. The strong synergistic effects between cationic polymers and antibiotics diminish the intrinsic resistance of the pathogens, thus leading to significantly enhanced antimicrobial efficacy, especially for AMR pathogens. Antibiotics will be conjugated onto the cationic polymer via pH- or ROS-responsive linkers as the inflammatory microenvironment in infected tissues have low pH levels and high levels of reactive oxygen species (ROS). Furthermore, we engineered a GSH-cleavable and charge-reversal cationic polymer that can greatly reduce its systemic toxicity as well as cellular toxicity for mammalian cells. Lastly, PDC capable of stimuli (disease-specific)- controlled drug release can accumulate preferentially at the infected tissues due to the enhanced permeation and retention (EPR) effect, thereby further reducing systemic toxicity while achieving high antimicrobial efficacy. In Aim 1, we will design, synthesize and characterize pH- and ROS-responsive PDCs. We will first investigate the synergy between a number of free (i.e., before conjugation) FDA-approved antibiotics and our uniquely designed stimuli-responsive and charge-reversal biocompatible cationic polymer. In Aim 2, the antimicrobial and antibiofilm efficacies, drug resistance development profiles, and biocompatibilities of the resulting stimuli- responsive PDCs will be evaluated in multiple bacteria species. In Aim 3, we will systematically determine the maximum tolerated dose, in vivo biodistribution, antimicrobial efficacy, and potential systemic toxicity of the selected PDCs in three clinically relevant bacterial infection mouse models. This study will create a new class of PDCs based on the unique biocompatible cationic polymer we engineered, various FDA-approved antibiotics, and a number of stimuli-responsive linkers, which can effectively combat the prevalent AMR crisis and offer a general, yet effective and safe, solution to treat many types of infections.

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。 我们的目标是开发创新、高效、生物相容性 pH 或 ROS 响应的抗菌聚合物 药物（即抗生素）结合物（PDC），可有效治疗严重感染性疾病并克服 AMR 同时确保高生物相容性，我们将利用 FDA 批准的现有抗生素来实现这一目标。 疾病特异性刺激和独特设计的生物相容性阳离子聚合物可以是。 有效的抗生素载体，因为它们可以在细菌壁/膜上诱导孔隙，从而显着增强 将抗生素输送到细菌中并允许它们绕过细菌中的外排泵 阳离子 PDC 还可以 (1) 粘附在细菌表面，从而充当药物储存库。 局部释放药物，(2)有效渗透细菌生物膜，从而导致抗生素更深的渗透。 阳离子聚合物和抗生素之间的强烈协同作用降低了细菌的内在耐药性 病原体，从而显着增强抗菌功效，特别是针对 AMR 病原体。 抗生素将通过 pH 或 ROS 响应性连接体缀合到阳离子聚合物上，作为炎症因子 受感染组织的微环境 pH 值较低，活性氧 (ROS) 水平较高。 此外，我们设计了一种 GSH 可裂解和电荷反转的阳离子聚合物，可以大大降低其 最后，PDC 能够刺激（疾病特异性）- 全身毒性以及对哺乳动物细胞的细胞毒性。 由于渗透性增强，受控药物释放可以优先在感染组织积聚 和保留（EPR）效应，进一步降低全身毒性，同时实现高抗菌功效。 在目标 1 中，我们将设计、合成和表征 pH 和 ROS 响应的 PDC。 FDA 批准的多种游离（即结合前）抗生素与我们独特的抗生素之间的协同作用 在目标 2 中，设计了刺激响应和电荷反转生物相容性阳离子聚合物。 抗菌膜功效、耐药性发展概况以及由此产生的刺激的生物相容性 在目标 3 中，我们将系统地确定响应性 PDC。 最大耐受剂量、体内生物分布、抗菌功效和潜在的全身毒性 在三种临床相关细菌感染小鼠模型中选择 PDC。 这项研究将基于我们设计的独特的生物相容性阳离子聚合物创建一类新型 PDC， 多种FDA批准的抗生素，以及多种刺激反应性连接物，可有效对抗 普遍存在的抗菌素耐药性危机，并提供一种通用但有效且安全的解决方案来治疗多种类型的感染。