Deferoxamine as adjunct therapeutics for tuberculosis
Abstract Iron is an essential element for the survival of both host and pathogens. Dysregulated iron metabolism is reported in tuberculosis patients, providing an opportunity for developing host-directed therapeutics. This study explored the antimycobacterial properties of an iron chelator, i.e. Deferoxamine (DFO), and its impact on limiting host iron onMycobacterium tuberculosis(Mtb) and infected C57BL/6 mice. A group of mice received ferric carboxymaltose to create an iron overload condition and aerosol infected with H37Rv Mtb. A subgroup of Mtb-infected mice received isoniazid (INH) and rifampicin (RIF) with or without DFO for tissue CFU assay and liver metabolite analysis using mass spectrometry. DFO was shown to have comparative antimycobacterial properties like INH inin-vitroconditions. Iron-overloaded mice exhibited significantly higher tissue (lungs, liver, spleen) mycobacterial burden at two weeks post-infection, and the efficacy of INH and RIF were compromised. Iron chelation by DFO alone significantly reduced the tissue mycobacterial burden at four weeks post-treatment and, as an adjunct to INH and RIF, significantly lowered lung mycobacterial load within the first and second weeks of treatment compared to the group that received INH and RIF. The intracellular pro-inflammatory cytokine (IFN-γ, TNF-α and IL-17A) levels in the lung CD4+T-cells of INH and RIF-treated groups with or without DFO were found to be similar. DFO with RIF and INH treatment significantly altered liver arginine biosynthesis, which has a direct role in neutralizing ammonia and has an immune-supportive role. Currently, DFO is used for treating acute iron toxicity and thalassemic patients with iron overload and holds promise as an adjunct therapeutic candidate for tuberculosis..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 25. Jan. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kaushik, Sandeep R. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.06.02.543389 |
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XBI039775690 |
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| 520 | |a Abstract Iron is an essential element for the survival of both host and pathogens. Dysregulated iron metabolism is reported in tuberculosis patients, providing an opportunity for developing host-directed therapeutics. This study explored the antimycobacterial properties of an iron chelator, i.e. Deferoxamine (DFO), and its impact on limiting host iron onMycobacterium tuberculosis(Mtb) and infected C57BL/6 mice. A group of mice received ferric carboxymaltose to create an iron overload condition and aerosol infected with H37Rv Mtb. A subgroup of Mtb-infected mice received isoniazid (INH) and rifampicin (RIF) with or without DFO for tissue CFU assay and liver metabolite analysis using mass spectrometry. DFO was shown to have comparative antimycobacterial properties like INH inin-vitroconditions. Iron-overloaded mice exhibited significantly higher tissue (lungs, liver, spleen) mycobacterial burden at two weeks post-infection, and the efficacy of INH and RIF were compromised. Iron chelation by DFO alone significantly reduced the tissue mycobacterial burden at four weeks post-treatment and, as an adjunct to INH and RIF, significantly lowered lung mycobacterial load within the first and second weeks of treatment compared to the group that received INH and RIF. The intracellular pro-inflammatory cytokine (IFN-γ, TNF-α and IL-17A) levels in the lung CD4+T-cells of INH and RIF-treated groups with or without DFO were found to be similar. DFO with RIF and INH treatment significantly altered liver arginine biosynthesis, which has a direct role in neutralizing ammonia and has an immune-supportive role. Currently, DFO is used for treating acute iron toxicity and thalassemic patients with iron overload and holds promise as an adjunct therapeutic candidate for tuberculosis. | ||
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