Cited by 220Tuberculosis Research and EpidemiologyMycobacterium research and diagnosisIron Metabolism and Disorders

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Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

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Olakanmi, Oyebode, Britigan, Bradley E., Schlesinger, Larry S.·2000·Infection and Immunity

DOI 10.1128/iai.68.10.5619-5627.2000PMC PMC101514

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Abstract

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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Evaluation of the effect of gallium maltolate on fecal Salmonella shedding in cattle.
Nerren, J., Edrington, T., Bernstein, L. R., Farrow, R., Genovese, K., Callaway, T. R., Anderson, R., Krueger, N., Duke, S. E., & Nisbet, D. J. (2011) · Journal of Food Protection · doi:10.4315/0362-028x.jfp-10-298 · Cited by 10
Free iron ions decrease indoleamine 2,3-dioxygenase expression and reduce IFNγ-induced inhibition of Chlamydia trachomatis infection
Krauße‐Opatz, B., Wittkop, U., Gutzki, F. M., Schmidt, C., Jürgens‐Saathoff, B., Meier, S., Beckmann, B., Takikawa, O., Morgan, M. A., Tsikas, D., et al. (2009) · Microbial Pathogenesis · doi:10.1016/j.micpath.2009.03.001 · Cited by 9
Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells
Olmo-Fontánez, A. M., Scordo, J. M., Schami, A., Garcia-Vilanova, A., Pino, P. A., Hicks, A., Mishra, R., Maselli, D. J., Peters, J., Restrepo, B. I., et al. (2024) · Mucosal Immunology · doi:10.1016/j.mucimm.2024.01.001 · Cited by 9
“For determination of intracellular M.tb by the CFUs method, infected ATs at MOI 10:1 were lysed and enumerated as described previously 11,59 .”
MethodSelf-citation
Beyond antibiotics for pulmonary nontuberculous mycobacterial disease.
Waterer, G. (2020) · Current opinion in pulmonary medicine · doi:10.1097/mcp.0000000000000665 · Cited by 9
“avium resident inside macrophages, in part as gallium is concentrated in the intracellular space of phagocytes [66].”
Background
Restoration of growth by manganese in a mutant strain of Escherichia coli lacking most known iron and manganese uptake systems
Taudte, N., German, N., Zhu, Y.-G., Grass, G., & Rensing, C. (2016) · Biometals · doi:10.1007/s10534-016-9927-3 · Cited by 9
“Generally, it was observed that iron-limitation promotes gallium-toxicity (Beriault et al. 2007; Kaneko et al. 2007; Olakanmi et al. 2000) and this was also the case for the iron/manganese-uptake mutant characterized in this study.”
Background
Vitamin Deficiency and Tuberculosis: Need for Urgent Clinical Trial for Managment of Tuberculosis
Banerjee, D. (2014) · Journal of Nutritional Health & Food Science · doi:10.15226/jnhfs.2014.00118 · Cited by 11
“Iron is essentially needed by Mycobacterium tuberculosis for almost all of its strategies for successful intracellular survival and pathogenecity in human hosts, including the activity of enzymes against oxidative burst, supply of oxygen to hypoxic atmosphere by mycobacterial truncated haemoglobins, arresting phagosom…”
Background
Gallium(III) Nitrate Inhibits Pathogenic Vibrio splendidus Vs by Interfering with the Iron Uptake Pathway.
Song, T., Zhao, X.-L., Shao, Y., Guo, M., Li, C.-H., & Zhang, W.-W. (2019) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.1903.03008 · Cited by 8
The Biofilm Formation onto Implants and Prosthetic Materials May Be Contrasted Using Gallium (3+)
Rimondini, L., Valle, C. D., Cochis, A., Azzimonti, B., & Chiesa, R. (2013) · doi:10.4028/www.scientific.net/kem.587.315 · Cited by 8
“The property of Ga 3+ to mimic and replace iron is called “Trojan horse” strategy [14] and can be exploited to disrupt iron metabolism in a wide range of bacteria, including mycobacteria [16], Pseudomonas aeruginosa [14], methicillin-resistant S.”
Background
The influence of gallium and other metal ions on the uptake of non-transferrin-bound iron by rat hepatocytes.
Sturm, B., Lassacher, U., Ternes, N., Jallitsch, A., Goldenberg, H., & Scheiber-Mojdehkar, B. (2006) · Biochimie · doi:10.1016/j.biochi.2005.12.001 · Cited by 8
Drug resistant Mycobacterium tuberculosis strains have altered cell envelope hydrophobicity that influences infection outcomes in human macrophages
Schami, A., Islam, M. N., Wall, M., Hicks, A., Meredith, R., Kreiswirth, B. N., Mathema, B., Belisle, J. T., & Torrelles, J. B. (2024) · Scientific Reports · doi:10.1038/s41598-024-81457-0 · Cited by 7
“Similarly, hMDM monolayers in wells were infected with a MOI of 1:1 to determine intracellular growth at 2, 24, 72, and 120 h post-infection (hpi) using the CFU method as described 42,47 .”
Emerging and alternative strategies for the treatment of nontuberculous mycobacterial infections
Sreekumar, A., Kumar, A., Biswas, R., & Biswas, L. (2024) · Expert Review of Anti-Infective Therapy · doi:10.1080/14787210.2024.2395003 · Cited by 7
“…iron metabolism, thereby hindering the growth of mycobacteria such as M. tuberculosis , M. avium , and M. abscessus , highlighting its therapeutic potential [136,137] These findings underscore the potential of small molecules in developing effective and specific therapies for NTM infections.”
Elevated temperature inhibits recruitment of transferrin-positive vesicles and induces iron-deficiency genes expression in Aiptasia pulchella host-harbored Symbiodinium
Song, P.-C., Wu, T., Hong, M., & Chen, M. (2015) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2015.05.005 · Cited by 11
The potential of drug repurposing to face bacterial and fungal biofilm infections
Oliveira, I. M., Borges, A. D. S., & Simões, M. V. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819497-3.00014-3 · Cited by 6
Old biomarkers in tuberculosis management: are they still useful? a systematic review
Fusani, L., Tersigni, C., Chiappini, E., Venturini, E., & Galli, L. (2021) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2021.1898945 · Cited by 6
Synthesis, characterization, and in vitro cytocompatibility of Ga-bioactive glass/polymer hydrogel composites
Keenan, T., Placek, L., Keenan, N. L., Hall, M., & Wren, A. W. (2016) · Journal of Biomaterials Applications · doi:10.1177/0885328216646655 · Cited by 6
Synchrotron X-Ray Fluorescence Microscopy of Gallium in Bladder Tissue following Gallium Maltolate Administration during Urinary Tract Infection
Ball, K. R., Sampieri, F., Chirino, M., Hamilton, D. L., Blyth, R. I. R., Sham, T., Dowling, P. M., & Thompson, J. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00616-13 · Cited by 7
“The mean tissue concentration in this study exceeds the concentrations required to inhibit growth of Pseudomonas aeruginosa and Mycobacterium tuberculosis in vitro, suggesting that oral administration of gallium maltolate can produce potentially clinically relevant gallium concentrations in homogenized bladder tissue…”
Background
Iron modulates the replication of virulent Mycobacterium bovis in resting and activated bovine and possum macrophages
Denis, M., & Buddle, B. M. (2005) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2005.04.010 · Cited by 5
Gallium and Gallium Semiconductor Compounds
Fowler, B., & Sexton, M. (2015) · doi:10.1016/b978-0-444-59453-2.00036-6 · Cited by 6
Iron Chelation in Chemotherapy
Weinberg, E. D. (2003) · Advances in applied microbiology · doi:10.1016/s0065-2164(03)01008-6 · Cited by 7
Reduction in absorption of gallium maltolate in adult horses following oral administration with food: chemistry and pharmacokinetics.
Pollina, G. F., Pepe, M., Dean, A., Marco, V. D., & Marton, D. (2013) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/jvp.12022 · Cited by 5
Coordination and Solution Chemistry of the Metals: Biological, Medical and Environmental Relevance
Brothers, P. J., & Ruggiero, C. E. (2011) · Wiley eBooks · doi:10.1002/9780470976548.ch9 · Cited by 7
Comment on: Resistance of planktonic and biofilm-grown Burkholderia cepacia complex isolates to the transition metal gallium.
Lechuga-Ballesteros, D., Truong-Le, V., & Patzer, E. (2009) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkp086 · Cited by 5
Improved cultural selectivity of medically significant fungi by suppression of contaminating bacterial flora employing gallium (III) nitrate.
Moore, J., Murphy, A., Millar, B., Loughrey, A., Rooney, P., Elborn, J., & Goldsmith, C. (2009) · Journal of Microbiological Methods · doi:10.1016/j.mimet.2008.09.018 · Cited by 5
Plant-based siderophore: a new avenue in molecular medicine for tuberculosis.
Dam, T., & Babu, C. R. (2003) · Journal of Medical Microbiology · doi:10.1099/jmm.0.05144-0 · Cited by 5
“In vitro growth studies using standard culture media indicate that siderophore-mediated iron acquisition plays a critical role in growth and metabolism of M. tuberculosis (Olakanmi et al., 2000).”
Background
Evaluation of serum iron and iron binding capacity in cows with paratuberculosis
Senturk, S., Metcitoglu, Z., Ülgen, M., Borum, E., Temizel, E., & Kasap, S. (2009) · Tierärztliche Praxis G: Großtiere/Nutztiere · doi:10.1055/s-0038-1623829 · Cited by 5
Combination of gallium citrate and levofloxacin induces a distinct metabolome profile and enhances growth inhibition of multidrug-resistant Mycobacterium tuberculosis compared to linezolid
Ilchenko, O., Nikolaevskaya, E., Zinchenko, O., Ivanytsia, V., Prat-Aymerich, C., Ramstedt, M., & Rzhepishevska, O. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1474071 · Cited by 4
HIV infection impairs the host response to Mycobacterium tuberculosis infection by altering surfactant protein D function in the human lung alveolar mucosaPreprint
Akhter, A., Moliva, J. I., Azad, A. K., Olmo-Fontánez, A. M., Garcia-Vilanova, A., Scordo, J. M., Gavrilin, M., Diaz, P. T., Endsley, J., Weintraub, S. T., et al. (2023) · bioRxiv · doi:10.1101/2023.10.01.560171 · Cited by 4
“Authors declare no conflict of interest.”
Self-citation
Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.
Monk, C., Sweeney, R., Bernstein, L., & Fecteau, M. (2016) · American Journal of Veterinary Research · doi:10.2460/ajvr.77.2.151 · Cited by 4
Efficacy of gallium maltolate against Lawsonia intracellularis infection in a rabbit model.
Sampieri, F., Allen, A., Alcorn, J., Clark, C., Vannucci, F., Pusterla, N., Mapes, S., Ball, K. R., Dowling, P. M., Thompson, J., et al. (2014) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/jvp.12132 · Cited by 4
“Thus, at sufficiently high concentrations, GaIII can be absorbed by bacteria, altering the first step of the bacterial ferric metabolism (Olakanmi et al., 2000).”
Background
Artemisia afra infusions clinical benefits as a complementary treatment to “WHO” approved drugs against tuberculosis
Bagire, P. G., Ogwang, P., Lusi, J. K., Lusi, J. P., Daddy, N. B., Kahatwa, S., Serugendo, A., & Kihemba, K. (2022) · Pharmacy & Pharmacology International Journal · doi:10.15406/ppij.2022.10.00379 · Cited by 3
Nanotechnology Based Therapeutics, Drug Delivery Mechanisms and Vaccination approaches for Countering Mycobacterium avium subspecies paratuberculosis (MAP) Associated Diseases
Bj, S., Sohal, J., Stephen, B. J., Jain, M., Dhama, K., Sv, S., Singh, S. V., Datta, M., Jain, N., Jayaraman, S., et al. (2015) · Asian Journal of Animal and Veterinary Advances · doi:10.3923/ajava.2015.830.842 · Cited by 3
Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits.
Sampieri, F., Alcorn, J., Allen, A., Clark, C., Vannucci, F., Pusterla, N., Mapes, S., Ball, K. R., Dowling, P. M., Thompson, J., et al. (2014) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/jvp.12114 · Cited by 3
Relating pH and Ion Release from Ga2O3-Na2O-CaO-ZnO-SiO2 Bioactive Glasses
Keenan, T., Wren, A., Coughlan, A., Towler, M., & Hall, M. (2013) · 2013 39th Annual Northeast Bioengineering Conference · doi:10.1109/nebec.2013.133 · Cited by 3
“Ga is included in these glasses because it has exhibited anti-bacterial properties [1], and anticancer abilities [2].”
Background
An innovative eco-friendly optical sensor designed specifically to detect gallium ions in environmental samples
Aljabri, M. D., El-Bahy, S. M., El-Sayed, R., Debbabi, K. F., Amin, A. S., & Mohamed, N. M. (2024) · Sensing and Bio-Sensing Research · doi:10.1016/j.sbsr.2024.100687 · Cited by 2
GALLIUM NANOPARTICLES AS DELIVERY SYSTEM AGAINST INFECTIOUS DISEASES AND CANCER
Mandal, A. (2020) · doi:10.36106/ijar/7012037 · Cited by 2
Transcriptomic Analysis of Shiga Toxin-Producing Escherichia coli FORC_035 Reveals the Essential Role of Iron Acquisition for Survival in Canola Sprouts and Water Dropwort
Na, H., Kim, Y., Kim, D., Yoon, H., & Ryu, S. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02397 · Cited by 2
Unraveling Resistance Mechanisms against New Antimicrobials Using Transposon Mutagenesis
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Main-Group Medicinal Chemistry Including Li and Bi
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The structural characterization of Ga2O3-Na2O-CaO-ZnO-SiO2 bioactive glasses
Keenan, T., Wren, A., Coughlan, A., Hall, M., & Towler, M. (2012) · Northeast Bioengineering Conference · doi:10.1109/nebc.2012.6207114 · Cited by 1
“Gallium was chosen because it has exhibited properties such as the ability to lower blood-calcium levels [3], inhibit bacterial growth [4], and also because it has exhibited anticancer abilities [5].”
Background
Ga3+ Replacing of Fe3+ as a “Trojan Horse” Antimicrobial Strategy: Modeling the Process within Bacterial Catalase–Peroxidase KatG
Gramolini, L., López-Corbalán, R., García-Millán, J., Kircheva, N., Marazzi, M., & García‐Iriepa, C. (2026) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6c02504
Mycobacterium tuberculosis subverts macrophage-mediated defense through exploitation of the Zn transporter ZIP8
Arnett, E., Lumbreras, M., Hernandez, E., Campos, D., Wager, C. M. L., Pahari, S., Matouba, D., Determann, B. F., Renshaw, C., Longstreet, B., et al. (2026) · iScience · doi:10.1016/j.isci.2026.116276
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Drosophila melanogaster as Model Organism to Assess Brake Dust Toxicity by a Multi-platform Approach.
Rosa, M. D., Vaccarella, E., Cerasti, F., Lucchesi, V., Marini, F., Massimi, L., Mastrantonio, V., Sciubba, F., Spagnoli, M., Porretta, D., et al. (2026) · Environmental Pollution · doi:10.1016/j.envpol.2026.127661
Gallium-Containing Bioactive Glasses: Their Influence on Ion Release and the Bioactivity of Resulting Glass Polyalkenoate Cements
Placek, L., Perry, D. L., Towler, M., & Wren, A. W. (2025) · Applied Sciences · doi:10.3390/app15147756
Retinoic Acid and Iron Metabolism: A Step Towards Design of a Novel Antitubercular Drug
Chakraborty, S., Bhattacharyya, R., Sayal, K., & Banerjee, D. (2014) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201015666141126121639 · Cited by 2
“[53] Olakanmi, O.”
Background

Authors: Olakanmi, O., Britigan, B. E., & Schlesinger, L. S.
Affiliations: United States Department of Veterans Affairs (US)
University of Iowa (US)
ORCID: Britigan, Bradley E.
Schlesinger, Larry S.
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
DOI: 10.1128/iai.68.10.5619-5627.2000
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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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Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

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