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，利用金属镓（Ga）作为“特洛伊木马”来破坏细菌的铁代谢。Ga具有与Fe几乎相同的离子半径，许多生物系统无法区分Ga和Fe。由于Ga3+不能还原，因此Ga破坏了铁依赖过程，氧化还原循环对铁的生物功能至关重要。我们建议开展转化工作，以研究Ga作为吸入式抗菌药物的潜力。我们提交了一份R01提案来资助这个项目，但是这个提案差一点就错过了资金水平。为了响应《美国复苏与再投资法案》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。通过适度增加预算（大约增加15%的直接成本），我们将能够完成原项目的大部分工作，同时在辛辛那提大学和华盛顿大学创造两个新的工作岗位，并挽救两个面临风险的工作岗位。我们进行的研究将继续构成一个具有意义的个人目标的连贯项目。此外，该项目继续实现进一步发展这种治疗肺部感染的新方法的转化目标。目标是：镓的作用机制是什么？我们将确定Ga如何阻断Fe摄取，找到Ga摄取途径，并使用独立的方法识别Ga的细胞内靶标。目标2。镓对CF痰液有效吗？镓耐药发生的频率有多高？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治疗铜绿假单胞菌感染的潜力。目标3。反复吸入镓安全吗？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。

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.