Rhodamine labeling of 3-hydroxy-4-pyridinone iron chelators is an important contribution to target Mycobacterium avium infection

Moniz, Tânia; Nunes, Ana; Silva, Ana M. G.; Queirós, Carla; Ivanova, Galya; Gomes, Maria Salomé; Rangel, Maria

doi:10.1016/j.jinorgbio.2013.01.002

Cited by 32 publications

(45 citation statements)

References 42 publications

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“…Chelators are able to restrict growth of Mycobacterium avium (46)(47)(48), while synthetic mycobactin analogues selectively inhibit M. tuberculosis growth (49). Additionally, iron chelation has proved to inhibit the cytotoxic effect of mycolactone, a macrolide toxin produced by Mycobacterium ulcerans, the causative agent of the necrotizing skin disease Buruli ulcer (50).…”

Section: Discussionmentioning

confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

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Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.

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Section: Discussionmentioning

confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

Dragset

Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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“…Bone marrow-derived macrophages (BMDM) were obtained as described previously 39 from the bone marrow of Fth1 +/+ or Fth1 −/− mice. Mice referred to as Fth1 −/− mice are conditional Fth1 deficient (Fth1 Fl/Fl ; Lyz2 cre/+ ) mice, obtained by crossing Fth1 Fl/Fl mice 17 with Lyz2 cre/+ mice.…”

Section: Macrophage Culturesmentioning

confidence: 99%

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Mesquita

Silva

Gomes

et al. 2020

Sci Rep

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Macrophages are central cells both in the immune response and in iron homeostasis. Iron is both essential and potentially toxic. Therefore, iron acquisition, transport, storage, and release are tightly regulated, by several important proteins. Cytosolic ferritin is an iron storage protein composed of 24 subunits of either the L-or the H-type chains. H-ferritin differs from L-ferritin in the capacity to oxidize fe 2+ to fe 3+ . In this work, we investigated the role played by H-ferritin in the macrophages' ability to respond to immune stimuli and to deal with exogenously added iron. We used mice with a conditional deletion of the H-ferritin gene in the myeloid lineage to obtain bone marrow-derived macrophages. These macrophages had normal viability and gene expression under basal culture conditions. However, when treated with interferon-gamma and lipopolysaccharide they had a lower activation of Nitric Oxide Synthase 2. Furthermore, H-ferritin-deficient macrophages had a higher sensitivity to ironinduced toxicity. This sensitivity was associated with a lower intracellular iron accumulation but a higher production of reactive oxygen species. These data indicate that H-ferritin modulates macrophage response to immune stimuli and that it plays an essential role in protection against iron-induced oxidative stress and cell death.Since macrophages and iron metabolism are tightly connected and H-ferritin is crucial for iron storage inside the cells, we hypothesized that H-ferritin has a key role in macrophages viability, development, activation, and iron handling. To test this hypothesis, we used mice with a conditional deletion of the H-ferritin gene (Fth1) in the myeloid lineage, generated from the H-ferritin-loxP mice created by Lukas Kuhn and collaborators 17 . We obtained bone marrow-derived macrophages (BMDM) from these mice and found that although in vitro macrophage differentiation proceeded normally, H-ferritin-deficient BMDM had subtle alterations in their response to immune stimulation and a marked increase in susceptibility to oxidative stress and cell death induced by exogenously added iron. Scientific RepoRtS |(2020) 10:3061 | https://doi.

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“…We have also shown that the addition of iron chelators to M. avium cultures, either in axenic culture, in macrophage cultures, or in vivo led to significant decreases in mycobacterial growth (Gomes et al, 1999a; Fernandes et al, 2010). Furthermore, we have developed new molecules based on the 3-hydroxy-4-pyridinone iron chelating moiety, in which the inclusion of a rhodamine residue improved anti-mycobacterial activity, presumably through improved intracellular distribution and targeting for the mycobacteria-containing phagosome (Fernandes et al, 2010; Nunes et al, 2010; Moniz et al, 2013). …”

Section: Iron Metabolism In Mycobacterium Infectionmentioning

confidence: 99%

Iron in intracellular infection: to provide or to deprive?

Silva‐Gomes

Vale-Costa

Appelberg

et al. 2013

Front. Cell. Infect. Microbiol.

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Due to their chemical versatility, transition metals were incorporated as cofactors for several basic metabolic pathways in living organisms. This same characteristic makes them potentially harmful, since they can be engaged in deleterious reactions like Fenton chemistry. As such, organisms have evolved highly specialized mechanisms to supply their own metal needs while keeping their toxic potential in check. This dual character comes into play in host-pathogen interactions, given that the host can either deprive the pathogen of these key nutrients or exploit them to induce toxicity toward the invading agent. Iron stands as the prototypic example of how a metal can be used to limit the growth of pathogens by nutrient deprivation, a mechanism widely studied in Mycobacterium infections. However, the host can also take advantage of iron-induced toxicity to control pathogen proliferation, as observed in infections caused by Leishmania. Whether we may harness either of the two pathways for therapeutical purposes is still ill-defined. In this review, we discuss how modulation of the host iron availability impacts the course of infections, focusing on those caused by two relevant intracellular pathogens, Mycobacterium and Leishmania.

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Rhodamine labeling of 3-hydroxy-4-pyridinone iron chelators is an important contribution to target Mycobacterium avium infection

Cited by 32 publications

References 42 publications

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Iron in intracellular infection: to provide or to deprive?

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