<i>Mycobacterium tuberculosis</i>
            Can Utilize Heme as an Iron Source

Jones, Christopher M.; Niederweis, Michael

doi:10.1128/jb.01312-10

Cited by 90 publications

(110 citation statements)

References 31 publications

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“…S2 B and C). These results ruled out the possibility that the previously observed lack of growth of Mtb siderophore mutants (15,19) was a result of insufficient amounts of soluble iron and demonstrated that low-affinity iron uptake is not capable of promoting the growth of Mtb in the absence of siderophores. This is consistent with the absence in Mtb of all known components of iron ion uptake systems of M. smegmatis, such as the putative ferric and ferrous inner membrane transporters and the Mycobacterium smegmatis porin A (MspA)-like porins in the outer membrane (20).…”

Section: Resultsmentioning

confidence: 43%

“…S1]. One possible explanation is that Mtb cannot use iron salts without siderophores, as observed previously with some siderophore biosynthesis mutants (15,16) but not with others (17). Even 100 mM ferric citrate failed to stimulate the growth of Mtb siderophore biosynthesis mutant ΔmbtD::hyg, whereas the Mycobacterium smegmatis siderophore biosynthesis mutant ΔfxbA::hygΔmbtD::kan (18) was rescued by 50 μM ferric citrate (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 85%

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Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Jones

Wells

Madduri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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102

106

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Siderophores are small iron-binding molecules secreted by bacteria to scavenge iron. Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis, produces the siderophores mycobactin and carboxymycobactin. Complexes of the mycobacterial membrane proteins MmpS4 and MmpS5 with the transporters MmpL4 and MmpL5 are required for siderophore export and virulence in Mtb.Here we show that, surprisingly, mycobactin or carboxymycobactin did not rescue the low-iron growth defect of the export mutant but severely impaired growth. Exogenous siderophores were taken up by the export mutant, and siderophore-delivered iron was used, but the deferrated siderophores accumulated intracellularly, indicating a blockade of siderophore recycling. This hypothesis was confirmed by the observation that radiolabeled carboxymycobactin was taken up and secreted again by Mtb. Addition of iron salts to an Mtb siderophore biosynthesis mutant stimulated more growth in the presence of a limiting amount of siderophores than iron-loaded siderophores alone. Thus, recycling enables Mtb to acquire iron at lower metabolic cost because Mtb cannot use iron salts without siderophores. Exogenous siderophores were bactericidal for the export mutant in submicromolar quantities. High-resolution mass spectrometry revealed that endogenous carboxymycobactin also accumulated in the export mutant. Toxic siderophore accumulation is prevented by a drug that inhibits siderophore biosynthesis. Intracellular accumulation of siderophores was toxic despite the use of an alternative iron source such as hemin, suggesting an additional inhibitory mechanism independent of iron availability. This study indicates that targeting siderophore export/recycling would deliver a one-two punch to Mtb: restricting access to iron and causing toxic intracellular siderophore accumulation.

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Section: Resultsmentioning

confidence: 43%

Section: Resultsmentioning

confidence: 85%

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Jones

Wells

Madduri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

106

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“…To obtain iron, M. tuberculosis synthesizes and secretes high-affinity ferric iron chelators (mycobactins) (33), and in vitro, it also utilizes heme as an iron source (18,34). Although essential, iron can also be toxic, due to the ability of Fe 2ϩ to catalyze the generation of deleterious oxygen radicals from normal products of aerobic metabolism thorough the Fenton reaction (12,17).…”

mentioning

confidence: 99%

A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

Pandey¹,

Rodríguez²

2012

Infect Immun

100

112

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ABSTRACTIron is an essential, elusive, and potentially toxic nutrient for most pathogens, includingMycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host.M. tuberculosisrequires specialized iron acquisition systems to replicate and cause disease. It also depends on a strict control of iron metabolism and intracellular iron levels to prevent iron-mediated toxicity. Under conditions of iron sufficiency,M. tuberculosisrepresses iron acquisition and induces iron storage, suggesting an important role for iron storage proteins in iron homeostasis.M. tuberculosissynthesizes two iron storage proteins, a ferritin (BfrB) and a bacterioferritin (BfrA). The individual contributions of these proteins to the adaptive response ofM. tuberculosisto changes in iron availability are not clear. By generating individual knockout strains ofbfrAandbfrB, the contribution of each one of these proteins to the maintenance of iron homeostasis was determined. The effect of altered iron homeostasis, resulting from impaired iron storage, on the resistance ofM. tuberculosistoin vitroandin vivostresses was examined. The results show that ferritin is required to maintain iron homeostasis, whereas bacterioferritin seems to be dispensable for this function.M. tuberculosislacking ferritin suffers from iron-mediated toxicity, is unable to persist in mice, and, most importantly, is highly susceptible to killing by antibiotics, showing that endogenous oxidative stress can enhance the antibiotic killing of this important pathogen. These results are relevant for the design of new therapeutic strategies againstM. tuberculosis.

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“…To test for Mt-DyP deferrochelatase activity, we utilized a mycobactindeficient M. tuberculosis strain, Mtb⌬mbtB, which has an interrupted mycobactin biosynthetic pathway to prevent siderophore-mediated iron acquisition (20,41) and cannot utilize Fe(III) in the absence of exogenous siderophore (mycobactin). Thus, Mtb⌬mbtB may only sequester iron via the heme uptake pathway.…”

mentioning

confidence: 99%

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

Contreras¹,

Joens

McMath³

et al. 2014

Journal of Biological Chemistry

119

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Background: Mycobacterium tuberculosis has a probable nanocompartment (Mt-Enc). Results: Mt-Enc self-assembles into a 60-subunit cage that encapsulates enzymes via their C-terminal tails, which remain active within Mt-Enc. Conclusion: Cargo proteins are potentially involved in host oxidative stress response, suggesting that enzyme encapulation may be a mechanism to evade host immune assault. Significance: Mt-Enc may be utilized as a novel therapeutic delivery mechanism.

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Mycobacterium tuberculosis Can Utilize Heme as an Iron Source

Cited by 90 publications

References 31 publications

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

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