Inability to detect mycobactin in Mycobacteria-infected tissues suggests an alternative iron acquisition mechanism by Mycobacteria in vivo

Lambrecht, Randall S.; Collins, Michael T.

doi:10.1006/mpat.1993.1022

Cited by 35 publications

(24 citation statements)

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“…(43,51) and Mycobacterium sp. (42). However, the Ton complex, which is absent in the exbB mutant, is probably implicated in the acquisition of iron sources other than DHBA, like all putative endogenous-exogenous siderophores and some host iron-containing compounds.…”

Section: Discussionmentioning

confidence: 98%

The Ton System, an ABC Transporter, and a Universally Conserved GTPase Are Involved in Iron Utilization by Brucella melitensis 16M

et al. 2004

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Brucella spp. are gram-negative intracellular facultative pathogens that are known to produce 2,3-dihydroxybenzoic acid (DHBA), a catechol siderophore that is essential for full virulence in the natural host. The mechanism of DHBA entry into Brucella and other gram-negative bacteria is poorly understood. Using mini-Tn5Kmcat mutagenesis, we created a transposon library of Brucella melitensis 16M and isolated 32 mutants with a defect in iron acquisition or assimilation. Three of these transposon mutants are deficient in utilization of DHBA. Analysis of these three mutants indicated that the ExbB, DstC, and DugA proteins are required for optimal assimilation of DHBA and/or citrate. ExbB is part of the Ton complex, and DstC is a permease homologue of an iron(III) ABC transporter; in gram-negative bacteria these two complexes are involved in the uptake of iron through the outer and inner membranes, respectively. DugA is a new partner in iron utilization that exhibits homology with the bacterial conserved GTPase YchF. Based on this homology, DugA could have a putative regulatory function in iron assimilation in Brucella. None of the three mutants was attenuated in cellular models or in the mouse model of infection, which is consistent with the previous suggestion that DHBA utilization is not required in these models.In various environments, iron is present in two states, and its availability is affected by pH and aeration. Fe(III) oxides present in aerobic conditions are very insoluble at neutral pH (recently reviewed in references 5 and 29). In contrast, Fe(II) is relatively soluble, and obtaining iron is a much easier task for bacteria growing anaerobically. The problems that bacteria face in acquiring sufficient iron from their surroundings are particularly acute for pathogens. Bacteria are able to deal with this iron restriction imposed by their environment, e.g., through the mechanism of ferric iron capture. They may produce iron(III)-scavenging siderophores or directly bind hemeand iron-containing compounds from the host.In an aerobic environment, the concentration of available iron(III) is so low that energy is required for transport of the iron. An energized high-affinity iron(III) (as well as heme and vitamin B 12 ) transporter is conserved in many gram-negative bacteria. This system is composed of different outer membrane-specific receptors, all of which are linked to an inner membrane complex that contains at least the TonB, ExbB, and ExbD proteins (35), and of a specific periplasmic binding protein associated with an ABC transporter. It has been proposed that the binding of a siderophore to the gated outer membrane receptor enhances the interaction of this receptor with TonB (11, 48). The energy required for TonB's gatekeeper activity is provided by the proton motive force, and ExbB and ExbD proteins are essential for this function (1,13,39). After this, the ferrisiderophore is transported into the cytoplasm by a specific periplasmic binding protein associated with an ABC transporter. In the cytoplasm, iro...

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Section: Discussionmentioning

confidence: 98%

The Ton System, an ABC Transporter, and a Universally Conserved GTPase Are Involved in Iron Utilization by Brucella melitensis 16M

et al. 2004

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“…This would be a particularly efficient strategy of iron acquisition in the context of infection, where up to 10 6 -10 9 bacteria are recovered from single lesions of infected lungs (37,38). Such a model may also explain why nearly undetectable amounts of MBT have been found in mycobacterial-infected tissue samples (39).…”

Section: Discussionmentioning

confidence: 99%

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Jones

Wells

Madduri

et al. 2014

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

100

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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“…The absence of mycobactin in M.tb-infected tissues suggests that alternate iron acquisition mechanisms may exist in vivo 13 . The same study demonstrated that at pH 6.2, the presence of host proteins transferrin and lactoferrin promoted the growth of M. paratuberculosis mycobactin auxotrophs in culture.…”

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confidence: 99%

“…This aspect cannot be explained by the simple dissociation of bound iron from transferrin and lactoferrin, which is known to occur maximally at pH 5.5-4.0 (ref. 13). Another recent study demonstrates that the recombinant BCG(mbtB)30 strain which is unable to synthesize both mycobactin and carboxymycobactin retains the ability to multiply and survive within macrophages over the initial days of infection 14 .…”

mentioning

confidence: 99%

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

et al. 2014

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Mycobacterium tuberculosis (M.tb), which requires iron for survival, acquires this element by synthesizing iron-binding molecules known as siderophores and by recruiting a host iron-transport protein, transferrin, to the phagosome. The siderophores extract iron from transferrin and transport it into the bacterium. Here we describe an additional mechanism for iron acquisition, consisting of an M.tb protein that drives transport of human holo-transferrin into M.tb cells. The pathogenic strain M.tb H37Rv expresses several proteins that can bind human holo-transferrin. One of these proteins is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rv1436), which is present on the surface of M.tb and its relative Mycobacterium smegmatis. Overexpression of GAPDH results in increased transferrin binding to M.tb cells and iron uptake. Human transferrin is internalized across the mycobacterial cell wall in a GAPDH-dependent manner within infected macrophages.

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Inability to detect mycobactin in Mycobacteria-infected tissues suggests an alternative iron acquisition mechanism by Mycobacteria in vivo

Cited by 35 publications

References 0 publications

The Ton System, an ABC Transporter, and a Universally Conserved GTPase Are Involved in Iron Utilization by Brucella melitensis 16M

The Ton System, an ABC Transporter, and a Universally Conserved GTPase Are Involved in Iron Utilization by Brucella melitensis 16M

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

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