Gallium Nitrate Is Efficacious in Murine Models of Tuberculosis and Inhibits Key Bacterial Fe-Dependent Enzymes
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Acquiring iron (Fe) is critical to the metabolism and growth of Mycobacterium tuberculosis. Disruption of Fe metabolism is a potential approach for novel antituberculous therapy. Gallium (Ga) has many similarities to Fe. Biological systems are often unable to distinguish Ga 3+from Fe 3+. Unlike Fe 3+, Ga 3+cannot be physiologically reduced to Ga 2+. Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth of M. tuberculosis in broth and within cultured human macrophages. We now report that Ga(NO 3)3 shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally with M. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO 3)3, or NaNO 3. All mice receiving saline or NaNO 3 died. All Ga(NO 3)3-treated mice survived.M. tuberculosis CFU in the lungs, liver, and spleen of the NaNO 3-treated or saline-treated mice were significantly higher than those in Ga-treated mice. When BALB/c mice were substituted for BALB/c SCID mice as a chronic (nonlethal) infection model, Ga(NO 3)3 treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga on M. tuberculosis ribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreased M. tuberculosis RR activity by 50 to 60%, but no additional decrease in RR activity was seen at Ga concentrations that completely inhibited mycobacterial growth. Ga decreased aconitase activity by 90%. Ga(NO 3)3 shows efficacy in murine M. tuberculosis infection and leads to a decrease in activity of Fe-dependent enzymes. Additional work is warranted to further define Ga's mechanism of action and to optimize delivery forms for possible therapeutic uses in humans.
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Control over iron homeostasis appears decisive for the course of M. tuberculosis infection.
“In conclusion, control over iron homeostasis appears to be decisive for the course of M. tuberculosis infection and attempt to modulate macrophage iron status or bacterial iron acquisition may be attractive strategies for novel treatment approach of this devastating infection in an era of rapidly emerging drug resistance (231, 232).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [231]
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References 39 · Cited by 70
Research works printed but not linked: 1
- [15]15. Bernstein LR. 2005. 31Ga therapeutic gallium compounds, p 259-277. In Gielen M, Tiekink ERT (ed), Metallotherapeutic drugs and metal-based diagnostic agents. John Wiley & Sons, Ltd, Chichester, United Kingdom.
- Authors
- Olakanmi, O., Kesavalu, B., Pasula, R., Abdalla, M. Y., Schlesinger, L. S., & Britigan, B. E.
- Affiliations
- Cincinnati VA Medical Center (US)
- Omaha VA Medical Center (US)
- The Ohio State University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2013-12
- Volume
- 57
- Issue
- 12
- Pages
- 6074-6080
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3837848
- OpenAlex
- W2087717904
- Cited by
- 70
- References
- 39
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 12 · 2023: 7 · 2022: 5 · 2021: 1 · 2020: 12 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lincoln (University of Nebraska) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- gallium nitrate, Mycobacterium tuberculosis, tuberculosis, iron acquisition, iron-dependent enzymes, ribonucleotide reductase, aconitase, tuberculosis treatment, mouse infection model, DNA replication
- MeSH terms
- Aconitate Hydratase, Animals, Antimetabolites, Antitubercular Agents, Bacterial Proteins, Disease Models, Animal, Gallium, Iron, Liver, Lung, Mice, Inbred BALB C, Mycobacterium tuberculosis, Ribonucleotide Reductases, Spleen, Tuberculosis, Pulmonary, Colony Count, Microbial, Survival Analysis, Mice, SCID, Mice
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