A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require Fe for growth. We have shown that a strategy that uses the metal gallium (Ga) to disrupt bacterial Fe metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of P. aeruginosa infections. These data, the fact that gallium nitrate (trade name, Ganite") is Food and Drug Administration (FDA) approved for intravenous (IV) administration, and the dearth of new antibiotics in development make Ga a promising new therapeutic for P. aeruginosa infections. We have shown in our initial phase 1b study in patient with cystic fibrosis chronically infected with P. aeruginosa that IV Ga is safe, well tolerated, has a good pharmacokinetic profile and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV Ga. Here we propose a proof of concept phase 2 clinical trial to confirm our prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV Ga in CF subjects infected with P. aeruginosa. Chronic P. aeruginosa airway infections are the major cause of death in these patients and few treatments exist.

Public Health Relevance

Our data shows that gallium (Ga) kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different model P. aeruginosa infections. We have also shown that Ga is safe and well tolerated in our phase 1b study in cystic fibrosis (CF) with preliminary evidence of clinical efficacy. We propose to assess efficacy of Ga in a proof of concept randomized controlled trial in this patient population which if successful, could provide a novel agent to fight chronic infections with P. aeruginosa in other disease settings beyond CF.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
2R01FD003704-03A1
Application #
8565239
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
2009-09-23
Project End
2017-06-30
Budget Start
2013-09-16
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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