Gallium, a potential new therapeutic for CF airway infections

在这里，我们研究了一种新的抗菌方法，使用金属镓（Ga）作为“特洛伊木马”，破坏细菌铁代谢。Ga与Fe的离子半径几乎相同，许多生物系统无法区分Ga和Fe。Ga破坏了Fe依赖的过程，因为Ga 3+不能被还原，并且氧化还原循环对于Fe的生物功能至关重要。我们提出了翻译工作，以调查潜在的镓作为吸入抗菌治疗。我们提交了一份R01提案来资助这个项目，但是这个提案几乎没有达到资助水平。为了响应美国复苏和再投资法案的资助机会，我们缩小了项目的范围，以便在2年内完成目标。通过要求适度增加预算（直接成本增加约15%），我们将能够完成原项目的大部分工作，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保留两个有风险的工作。我们进行的研究将继续包括一个连贯的项目，有意义的个人目标。此外，该项目继续实现进一步开发这种新型肺部感染治疗方法的转化目标。目标是：目标1。镓的作用机制是什么？我们将确定如何镓块铁摄取，发现镓摄取途径，并确定使用独立的方法的镓细胞内的目标。目标2.镓对CF痰有效吗？镓耐药性发生的频率如何？常规抗生素是否能增强其活性？这些临床前研究将有助于优化Ga作为铜绿假单胞菌感染治疗的潜力。目标3。反复吸入镓是否安全？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。

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.