Advancing innovative therapies against pandrug-resistant Gram-negative superbugs

推进针对全耐药革兰氏阴性超级细菌的创新疗法

• 批准号: 10189507
• 负责人: Jian Li
• 金额: $ 64.62万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189507
• 关键词: 3-Dimensional; Acinetobacter baumannii; Address; Adverse effects; Aerosols; Amikacin; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Bronchial Spasm; Cells; Ciprofloxacin; Clinic; Clinical; Clinical Research; Colistin; Combined Antibiotics; Combined Modality Therapy; Confocal Microscopy; Coughing; Data; Development; Dose; Dose-Limiting; Drug Exposure; Drug Kinetics; Encapsulated; Epithelial; Epithelial Cells; Evolution; Fluorescence Microscopy; Formulation; Fourier Transform; Freeze Drying; Funding; Health; Human; Image; Imaging Techniques; In Vitro; Infection; Inhalation; Inhalation Therapy; Innovative Therapy; Ions; Klebsiella pneumoniae; Lead; Liposomes; Lower Respiratory Tract Infection; Lung; Lung infections; Mass Spectrum Analysis; Mesylates; Metals; Microbial Biofilms; Modeling; Monte Carlo Method; Multi-Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; Nebulizer; Penetration; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Polymers; Polymyxin Resistance; Polymyxins; Powder dose form; Prodrugs; Production; Pseudomonas aeruginosa; Pulmonary Tuberculosis; Regimen; Research Priority; Resistance; Resort; Respiratory Tract Infections; Rodent; Roentgen Rays; Route; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Superbug; Surface; Synchrotrons; System; Techniques; Technology; Tissue Model; Toxic effect; Translating; Treatment Efficacy; United States National Institutes of Health; Variant; Work; World Health Organization; amphiphilicity; antimicrobial; base; combat; compliance behavior; controlled release; dosage; drug disposition; drug inhalation; effective therapy; efficacious treatment; global health; imaging system; in vivo; innovation; interdisciplinary approach; multidisciplinary; nanoscale; nephrotoxicity; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; public health relevance; respiratory; success; treatment strategy

The World Health Organization (WHO) has recently listed Gram-negative ‘superbugs’ Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii as the most critical pathogens, which are the greatest threat to human health. Due to the slow progress in development of novel antibiotics, polymyxins are often used as the last-line therapy against Gram-negative infections; however, clinical studies have shown that the efficacy of parenteral polymyxins is disappointing for the treatment of Gram-negative lung infections due to very low exposure of the drug to the infection site at the airway surface and dose-limiting kidney toxicity. More worrying is the development of polymyxin resistance induced by the polymyxin monotherapy. One of the promising strategies for the treatment of Gram-negative lung infections is direct delivery of synergistic polymyxin combinations to the infection sites at the airway surface. However, conventional nebulization has low delivery efficiency; even worse, current colistin methanesulfonate (CMS) nebulization therapies are empirical and have never been systematically optimized using pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD). The overall aim of this project is to develop novel liposomal therapies for combinational antibiotics using innovative spray-freeze-drying powder production technology, cutting-edge imaging, systems pharmacology and mechanism-based pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD) modeling. The Specific Aims are: (1) to develop novel liposomal formulations of polymyxin combinations using innovative spray-freeze- drying technology; (2) to determine in vitro pharmacodynamics of the formulations; (3) to elucidate the disposition of polymyxin combinations from the formulations in the airway using cutting-edge imaging and the mechanisms of potential pulmonary toxicities using systems pharmacology; (4) to apply mechanism-based PK/PD/TD modeling to optimizing dosage regimens of the superior liposomal formulation in rodent lung infection models. To combat the emergent global antimicrobial crisis, we must outpace the evolution of ‘superbugs’ by novel strategies. With the disappointing progress in developing new antibiotic against MDR Gram-negative pathogens, our innovative multi-disciplinary project addresses NIAID’s strategic approach “extending the clinical utility of antibacterial drugs̸optimizing use of existing drugs and combination therapies to suppress emergence of resistance and minimize toxicity”. The success of our work will have a broader impact to the USA and global health as the platform can be readily applied to develop superior new therapies for other respiratory infections such as pulmonary tuberculosis.

世界卫生组织（WHO）最近将革兰氏阴性“超级细菌”肺炎克雷伯菌列入名单， 铜绿假单胞菌和鲍曼不动杆菌是最重要的致病菌，是最大的致病菌。 对人类健康的威胁。由于新型抗生素的开发进展缓慢，经常使用多粘菌素 作为对抗革兰氏阴性菌感染的最后一线疗法；但临床研究表明，其功效 肠外多粘菌素对革兰氏阴性肺部感染的治疗效果令人失望，因为其浓度非常低。 药物暴露于气道表面的感染部位和剂量限制性肾毒性。更令人担忧 是由多粘菌素单一疗法引起的多粘菌素耐药性的发展。有希望的之一 治疗革兰氏阴性肺部感染的策略是直接递送协同多粘菌素 组合到气道表面的感染部位。然而，传统雾化的输送量较低 效率;更糟糕的是，目前的甲磺酸粘菌素 (CMS) 雾化疗法是经验性的，并且 从未使用药代动力学/药效学/毒效动力学（PK/PD/TD）进行系统优化。 该项目的总体目标是开发用于组合抗生素的新型脂质体疗法 创新的喷雾冷冻干燥粉末生产技术、尖端成像、系统药理学和 基于机制的药代动力学/药效学/毒效动力学（PK/PD/TD）建模。具体 目标是：（1）使用创新的喷雾冷冻技术开发多粘菌素组合的新型脂质体制剂 干燥技术； (2)测定制剂的体外药效学； (3) 阐明处置 使用尖端成像和机制研究气道制剂中的多粘菌素组合 使用系统药理学研究潜在的肺部毒性； (4)应用基于机制的PK/PD/TD 在啮齿动物肺部感染模型中建立模型以优化优质脂质体制剂的剂量方案。 为了应对新出现的全球抗菌危机，我们必须以新颖的方式超越“超级细菌”的进化 策略。随着针对耐多药革兰氏阴性病原体的新型抗生素的开发进展令人失望， 我们创新的多学科项目解决了 NIAID 的战略方法“扩展临床 抗菌药物的效用——优化现有药物和联合疗法的使用以抑制 抗性的出现并最大限度地减少毒性”。我们工作的成功将对 美国和全球健康作为平台可以很容易地应用于为其他国家开发优质的新疗法 呼吸道感染，例如肺结核。