Journal article
Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections
Science translational medicine, Vol.10(460), eaat7520
09/26/2018
DOI: 10.1126/scitranslmed.aat7520
PMCID: PMC6637966
PMID: 30257953
Abstract
The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic
airway infections. Our results show that micromolar concentrations of gallium inhibited
growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic
lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.
Details
- Title: Subtitle
- Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections
- Creators
- Christopher H Goss - University of WashingtonYukihiro Kaneko - Osaka City UniversityLisa Khuu - University of WashingtonGail D Anderson - University of WashingtonSumedha Ravishankar - University of WashingtonMoira L Aitken - University of WashingtonNoah Lechtzin - Johns Hopkins MedicineGuolin Zhou - University of ChicagoDaniel M Czyz - University of ChicagoKathryn McLean - University of WashingtonOyebode Olakanmi - University of Cincinnati Medical CenterHoward A Shuman - University of ChicagoMary Teresi - University of Nebraska at OmahaEllen Wilhelm - University of WashingtonEllen Caldwell - University of WashingtonStephen J Salipante - University of WashingtonDouglas B Hornick - University of Nebraska at OmahaRichard J Siehnel - University of WashingtonLev Becker - University of ChicagoBradley E Britigan - University of IowaPradeep K Singh - University of Washington
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.10(460), eaat7520
- DOI
- 10.1126/scitranslmed.aat7520
- PMID
- 30257953
- PMCID
- PMC6637966
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Grant note
- K24 HL102246 / NHLBI NIH HHS R01 HL085868 / NHLBI NIH HHS P30 DK089507 / NIDDK NIH HHS R01 AI101307 / NIAID NIH HHS R01 FD003704 / FDA HHS UM1 HL119073 / NHLBI NIH HHS
- Language
- English
- Date published
- 09/26/2018
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984359699002771
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