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）最近列出了革兰氏阴性的“超级细菌”肺炎克雷伯菌，