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.
New antimicrobial agents are needed due to increasing antibiotic resistance and because antibiotics work poorly against the biofilms that cause chronic infections. This translational proposal explores a promising antimicrobial approach that may be useful against antibiotic resistant bacteria and biofilms.
