Gallium, a potential new therapeutic for CF airway infections

镓，一种治疗 CF 气道感染的潜在新疗法

• 批准号: 7851395
• 负责人: PRADEEP k SINGH
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851395
• 关键词: Acute; Aerobic; American; Animals; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biological Process; Breathing; Budgets; Cells; Chelating Agents; Chronic; Clinical; Communities; Cystic Fibrosis; DNA biosynthesis; Data; Development; Direct Costs; Drug Kinetics; Electron Transport; Environment; Enzymes; Equus caballus; FDA approved; Funding; Funding Opportunities; Gallium; Growth; Hospitals; Host Defense; Individual; Infection; Inhalation Toxicology; Intervention; Iron; Knowledge; Life; Link; Lung; Mediating; Metabolism; Metals; Microbial Biofilms; Modeling; Multi-Drug Resistance; Mus; Mutation; Occupations; Organism; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Pneumonia; Process; Pseudomonas aeruginosa; Radial; Recovery; Resistance; Risk; Role; Safety; Sepsis; Sputum; Stress; System; Testing; Time; Toxicology; Universities; Washington; Work; Wound Infection; antimicrobial; antimicrobial drug; bacterial resistance; combat; cystic fibrosis airway; cystic fibrosis patients; drug resistant bacteria; in vivo; killings; mortality; mucoid; novel; novel strategies; novel therapeutics; pathogen; preclinical study; prevent; response; secondary infection; uptake

Here we investigate a novel antimicrobial approach using the metal gallium (Ga) as a "Trojan horse" to disrupt bacterial Fe metabolism. Ga has a nearly identical ionic radius as Fe, and many biologic systems are unable to distinguish Ga from Fe. Ga disrupts Fe dependent processes because Ga3+ cannot be reduced, and redox cycling is critical for Fe's biological functions. We propose translational work to investigate the potential of Ga as an inhaled antimicrobial treatment. We submitted a R01 proposal to fund this project however this proposal narrowly missed the funding level. In response to the American Recovery and Reinvestment Act funding opportunity we have reduced the scope of our project so that the aims may be accomplished in a 2 year period. By requesting a modest increase in the budget (approximately a 15% increase in direct costs), we will be able to accomplish much of the work in the original project, while at the same time creating two new jobs and saving two at-risk jobs at the Universities of Cincinnati and Washington. The studies we perform will continue to comprise a coherent project with meaning individual aims. Furthermore the project continues to achieve the translational objective of furthering development of this novel treatment for lung infections. The aims are: Aim 1. What is gallium's mechanism of action? We will determine how Ga blocks Fe uptake, find Ga uptake pathways, and identify intracellular targets of Ga using independent approaches. Aim 2. Is gallium effective in CF sputum, how frequently does gallium resistance occur, and do conventional antibiotics enhance its activity? These preclinical studies will help optimize the potential of Ga as a treatment for P. aeruginosa infections. Aim 3. Is repeated gallium inhalation safe? We will perform chronic exposure studies in mice to gauge the safety of inhaled Ga.

在这里，我们研究了一种新型的抗菌剂方法，使用金属甘油（GA）作为“特洛伊木马”，以破坏细菌FE代谢。 GA的离子半径与Fe相同，许多生物系统无法将GA与Fe区分开。 GA会破坏FE依赖性过程，因为GA3+无法减少，氧化还原循环对于FE的生物学功能至关重要。我们提出了翻译工作，以研究GA作为吸入的抗菌治疗的潜力。我们提交了一项R01提案来为该项目提供资金，但是该提案差一点错过了资金水平。为了回应《美国恢复和再投资法》的资助机会，我们减少了项目范围，因此目标可以在两年内实现。通过要求预算适度增加（直接成本大约增加15％），我们将能够完成原始项目中的大部分工作，同时创造两个新的就业机会，并在辛辛那提大学和华盛顿大学节省两个高风险的工作。我们执行的研究将继续构成一个连贯的项目，这意味着个人目标。此外，该项目继续实现促进这种新型肺部感染治疗方法的转化目标。目的是：目标1。伽罗力的作用机理是什么？我们将使用独立的方法来确定GA如何阻止Fe吸收，找到GA吸收途径并确定GA的细胞内靶标。 AIM 2。甘露在CF痰中有效，耐甘油耐药性多久发生一次，并且常规抗生素会增强其活性吗？这些临床前研究将有助于优化GA作为铜绿假单胞菌感染的治疗潜力。 AIM 3。重复吸入的耐加仑安全吗？我们将在小鼠中进行慢性暴露研究，以评估吸入GA的安全性。