Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages
Open accessAbstract
Mycobacterium tuberculosis and M. avium complex (MAC) enter and multiply within monocytes and macrophages in phagosomes. In vitro growth studies using standard culture media indicate that siderophore-mediated iron (Fe) acquisition plays a critical role in the growth and metabolism of both M. tuberculosis and MAC. However, the applicability of such studies to conditions within the macrophage phagosome is unclear, due in part to the absence of experimental means to inhibit such a process. Based on the ability of gallium (Ga 3+) to concentrate within mononuclear phagocytes and on evidence that Ga disrupts cellular Fe-dependent metabolic pathways by substituting for Fe 3+and failing to undergo redox cycling, we hypothesized that Ga could disrupt Fe acquisition and Fe-dependent metabolic pathways of mycobacteria. We find that Ga(NO 3)3 and Ga-transferrin produce an Fe-reversible concentration-dependent growth inhibition of M. tuberculosis strains and MAC grown extracellularly and within human macrophages. Ga is bactericidal for M. tuberculosis growing extracellularly and within macrophages. Finally, we provide evidence that exogenously added Fe is acquired by intraphagosomal M. tuberculosis and that Ga inhibits this Fe acquisition. Thus, Ga(NO 3)3 disruption of mycobacterial Fe metabolism may serve as an experimental means to study the mechanism of Fe acquisition by intracellular mycobacteria and the role of Fe in intracellular survival. Furthermore, given the inability of biological systems to discriminate between Ga and Fe, this approach could have broad applicability to the study of Fe metabolism of other intracellular pathogens.
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Mycobacterium tuberculosis disrupts phagolysosomal maturation, an iron-dependent process critical for pathogen survival.
“Inside the macrophage, Mtb disrupts phagolysosomal maturation, an iron-dependent process critical for pathogen survival (Olakanmi et al., 2000).”
From Iron in infection and immunity (2013) · cites this paper as Olakanmi et al., 2000
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“MDM monolayers were prepared as above and cultured an additional 7 days in RH plus 20% autologous serum at 37◦C with 5%CO2 (Olakanmi et al. 2000).”
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“Furthermore, it has been demonstrated that gallium compounds, such as Ga(NO3)3 (gallium nitrate III), have antibacterial effects against Mycobaterium (Olakanmi et al., 2000), Francisella tulerens (Olakanmi et al.”
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“, Legionella pneumophila, and Mycobacterium tuberculosis must acquire iron from their host cell in order to replicate (1, 18, 20, 22).”
BackgroundHarnessing the power of fungal siderophores for the imaging and treatment of human diseases
Szebesczyk, A., Olshvang, E., Shanzer, A., Carver, P., & Gumienna-Kontecka, E. (2016) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2016.05.001 · Cited by 46 · see citing works
Mycobacterium avium Infection and Modulation of Human Macrophage Gene Expression
Greenwell-Wild, T., Vázquez, N., Sim, D. L., Schito, M., Chatterjee, D., Orenstein, J., & Wahl, S. (2002) · Journal of Immunology · doi:10.4049/jimmunol.169.11.6286 · Cited by 46
“Increased virulence may also be associated with increased gene expression of the transferrin receptor for requisite iron transport (60), and transient increases in the free radical scavenging enzyme superoxide dismutase (2 h) may represent a potential mode of macrophage self-preservation, but also protect the mycobact…”
BackgroundGuirado, E., Rajaram, M. V. S., Chawla, A., Daigle, J., Perle, K. L. L., Arnett, E., Turner, J., & Schlesinger, L. (2018) · Tuberculosis · doi:10.1016/j.tube.2018.06.012 · Cited by 45
“At the indicated times, macrophages were lysed as previously described [16] and M.”
MethodSelf-citationOlakanmi, O., Gunn, J., Su, S.-C., Soni, S., Hassett, D., & Britigan, B. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00655-09 · Cited by 45 · see citing works
“Fe acquisition from citrate was far greater than from either Tf or Lf in MDMs, a pattern that was also seen to a smaller degree with growth in Fe-limited medium.”
BackgroundInfluentialSelf-citationZhou, L., Deng, Y., Ren, Y.-J., Poon, H.-L., Chu, W.-Y., Wang, H., & Chan, Y.-K. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.148978 · Cited by 44 · see citing works
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“Gallium salts are used in pharmaceutical applications for hypercalcemia, and there is also evidence of a gallium therapeutic effect against syphilis, trypanosomiasis, and tuberculosis [14].”
BackgroundLong-acting antituberculous therapeutic nanoparticles target macrophage endosomes
Edagwa, B. J., Guo, D.-W., Puligujja, P., Chen, H., McMillan, J., Liu, X.-M., Gendelman, H., & Narayanasamy, P. (2014) · The FASEB Journal · doi:10.1096/fj.14-255786 · Cited by 44 · see citing works
“Mycobacterium infection was determined by counting colony-forming units (CFU) as described previously (44).”
MethodValappil, S., Coombes, M., Wright, L., Owens, G., Lynch, R. J., Hope, C., & Higham, S. (2012) · Acta Biomaterialia · doi:10.1016/j.actbio.2012.01.017 · Cited by 43 · see citing works
“The chelating agent was added to the medium to ensure any free iron in the medium, which could interfere with the antimicrobial effect of gallium [23], was chelated [22].”
BackgroundZheng, Q., Ding, F., Hu, X.-J., Feng, J., Shen, J.-L., & He, X.-J. (2021) · Bioorganic chemistry (Print) · doi:10.1016/j.bioorg.2021.104746 · Cited by 41
Choi, S.-R., Hassan, M., Britigan, B. E., & Narayanasamy, P. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46080541 · Cited by 40 · see citing works
“In M. tuberculosis , several genes have been identified that are involved in heme uptake, allowing the mycobacterium to use heme as an alternative iron source.”
BackgroundSelf-citationGallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus
Abdalla, M. Y., Switzer, B., Goss, C., Aitken, M., Singh, P., & Britigan, B. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00331-15 · Cited by 40 · see citing works
“tuberculosis and other bacteria that grow intra- or extracellularly (20, 26, 27).”
BackgroundMethodSelf-citationWelsh, C. T., Summersgill, J., & Miller, R. (2004) · Infection and Immunity · doi:10.1128/iai.72.3.1512-1518.2004 · Cited by 40
“lated and cultured based upon previously published methods (34).”
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Connor, M. G., Pulsifer, A. R., Chung, D., Rouchka, E., Ceresa, B. K., & Lawrenz, M. (2018) · mBio · doi:10.1128/mbio.01800-17 · Cited by 38
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“Gallium did not show cytotoxicity in the macrophage at concentrations up to 2 mM for up to 37 days [86].”
BackgroundIn vitro antimicrobial activity of gallium maltolate against virulent Rhodococcus equi.
Coleman, M., Kuskie, K., Liu, M., Chaffin, K., Libal, M., Giguère, S., Bernstein, L., & Cohen, N. (2010) · Veterinary Microbiology · doi:10.1016/j.vetmic.2010.05.027 · Cited by 36
“While the MIC data reported here do not tell us about intracellular concentrations, it is expected that gallium would concentrate in inflammatory cells such as macrophages (Olakanmi et al., 2000) The emergence of R.”
BackgroundInfluentialEvgS/EvgA, the unorthodox two-component system regulating bacterial multiple resistance
Zhang, R., & Wang, Y. (2023) · Applied and Environmental Microbiology · doi:10.1128/aem.01577-23 · Cited by 35 · see citing works
“Gallium nitrate is an antimicrobial agent that disrupts the iron metabolism in bacteria (101).”
BackgroundChoi, S.-R., Britigan, B., & Narayanasamy, P. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02643-18 · Cited by 35 · see citing works
“Ga (III)-based compounds, in the form of salts or complexed with other compounds, have shown broad-spectrum antimicrobial activity against mycobacteria and Gram-negative and Gram-positive bacteria (18, 32).”
BackgroundSelf-citationInnovative approaches to treat Staphylococcus aureus biofilm-related infections.
Richter, K., Vandendriessche, F., & Coenye, T. (2017) · Essays in Biochemistry · doi:10.1042/ebc20160056 · Cited by 35 · see citing works
Designing Ga(III)-containing hydroxyapatite with antibacterial activity
Kurtjak, M., Vukomanović, M., Krajnc, A., Kramer, L., Turk, B., & Suvorov, D. (2016) · doi:10.1039/c6ra23424k · Cited by 35
Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages
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Chemoprophylactic Antimicrobial Activity of Gallium Maltolate against Intracellular Rhodococcus equi
Martens, R., Miller, N. A., Cohen, N., Harrington, J. R., & Bernstein, L. (2007) · doi:10.1016/j.jevs.2007.06.007 · Cited by 35
“Gallium (Ga) is a trivalent semimetallic element that mimics Fe3þ: it binds to ferric sites on transferrin, is acquired from transferrin by certain bacteria, and is preferentially taken up by mononuclear phagocytes at sites of inflammation.(12,13) Unlike Fe3þ, however, Ga is not reducible to a divalent form under phys…”
BackgroundNontuberculous Mycobacterial Infections in Cystic Fibrosis.
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Genetic analysis of petrobactin transport in Bacillus anthracis
Carlson, P. E., Dixon, S. D., Janes, B. K., Carr, K. A., Nusca, T., Anderson, E. C., Keene, S. E., Sherman, D., & Hanna, P. (2010) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.07025.x · Cited by 30 · see citing works
“Gallium is toxic to most bacterial cells and transport of siderophore–gallium complexes across the membrane often leads to cell death (Olakanmi et al., 2000; Banin et al., 2008).”
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Arunachalam, K., Krishnan, G., Sethuraman, S., Abraham, S., Krishnan, S., Venkateswar, A., Arunkumar, J., Shi, C.-L., & MubarakAli, D. (2023) · Pathogens · doi:10.3390/pathogens12020270 · Cited by 29 · see citing works
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“crobial effect of gallium nitrate (14).”
Self-citationTherapeutic potential of iron chelators in diseases associated with iron mismanagement
Weinberg, E. D. (2006) · The Journal of pharmacy and pharmacology · doi:10.1211/jpp.58.5.0001 · Cited by 29 · see citing works
“Gallium, for example, is both microbicidal (Olakanmi et al 2002) and antineoplastic (Chitambar 2004).”
BackgroundIron limitation in M. tuberculosis has broad impact on central carbon metabolism
Theriault, M., Pisu, D., Wilburn, K. M., Lê-Bury, G., MacNamara, C. W., Petrassi, H., Love, M., Rock, J., VanderVen, B. C., & Russell, D. (2022) · Communications Biology · doi:10.1038/s42003-022-03650-z · Cited by 27 · see citing works
- Authors
- Olakanmi, O., Britigan, B. E., & Schlesinger, L. S.
- Affiliations
- United States Department of Veterans Affairs (US)
- University of Iowa (US)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2000-10
- Volume
- 68
- Issue
- 10
- Pages
- 5619-5627
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC101514
- OpenAlex
- W2161032017
- Cited by
- 220
- References
- 57
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 12 · 2023: 13 · 2022: 10 · 2021: 7 · 2020: 11 · 2019: 13 · 2018: 7 · 2017: 9 · 2016: 16 · 2015: 8 · 2014: 10 · 2013: 15 · 2012: 8
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (AI24954, 5r01hl051990-05, AI43870, AI33004)
- National Heart, Lung, and Blood Institute (HL-51990)
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases (AI 33004, AI 24954)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- gallium, iron acquisition, siderophores, Mycobacterium tuberculosis, Mycobacterium avium complex, macrophages, phagosome, intracellular mycobacteria, iron metabolism, bactericidal activity, gallium nitrate, intracellular survival
- MeSH terms
- Cells, Cultured, Culture Media, Gallium, Humans, Iron, Macrophages, Microscopy, Electron, Scanning, Monocytes, Mycobacterium tuberculosis, Transferrin, Mycobacterium avium Complex, Macrophages, Alveolar
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