Disruption of Mycobactin Biosynthesis Leads to Attenuation of Mycobacterium tuberculosis for Growth and Virulence

Reddy, P. Vineel; Puri, Rupangi Verma; Chauhan, Priyanka; Kar, Ritika; Rohilla, Akshay; Khera, Aparna; Tyagi, Anil K.

doi:10.1093/infdis/jit250

Cited by 111 publications

(114 citation statements)

References 45 publications

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“…Considering the fact that hemin is an abundant iron source in mammals (42) and can be used by Mtb (15), it is likely that self-poisoning by intracellularly accumulating siderophores contributes to the virulence defect of the export mutant. Recently, the virulence of an mbtE mutant, which did not produce siderophores anymore, was examined in guinea pigs (43). However, interpretation of these results is difficult because guinea pigs infected with the Mtb mbtE mutant showed the same pathology as those infected with wt Mtb 4 wk after infection, although no bacteria were recovered from organs infected with the mbtE mutant, as discussed elsewhere (44).…”

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.

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: 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.

102

106

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“…Mutants lacking the biosynthetic genes ybtS, ybtE, irp1, or ybtU do not produce Ybt (Supplemental NRPS/PKS systems, which are notable in infectious diseases as the source of antibiotics such as mupirocin, tetracyclines, and macrolides, but also the source of many virulence-associated siderophores such as pyochelin in Pseudomonas aeruginosa and mycobactin in Mycobacterium tuberculosis (20)(21)(22). NRPS and PKS pathways are characterized by their thiotemplating, assembly line mechanism, whereby all substrates and intermediates are covalently attached to phosphopantetheinylated carrier protein (CP) domains as they proceed through the catalytic domains of large, multimodular biosynthetic enzymes.…”

Section: Introductionmentioning

confidence: 99%

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

Ohlemacher¹,

Giblin²,

d’Avignon³

et al. 2017

Journal of Clinical Investigation

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“…On one hand, rapid withdrawal of accessible iron is the most prominent example of "nutritional immunity"; on the other hand, iron deficiency in the host is a signal for pathogens to induce the expression of toxins and other virulence factors in conjunction with iron acquisition systems (5). To obtain iron, M. tuberculosis synthesizes and secretes high-affinity iron chelators or siderophores named mycobactins, which are essential for virulence (6,7). Two forms of mycobactins are produced: carboxymycobactin, an amphiphilic molecule that is secreted into the medium, and mycobactin, a lipophilic molecule that remains cell associated (8).…”

mentioning

confidence: 99%

Role for Mycobacterium tuberculosis Membrane Vesicles in Iron Acquisition

et al. 2014

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dMycobacterium tuberculosis releases membrane vesicles packed with molecules that can modulate the immune response. Because environmental conditions often influence the production and content of bacterial vesicles, this study examined M. tuberculosis microvesicles released under iron limitation, a common condition faced by pathogens inside the host. The findings indicate that M. tuberculosis increases microvesicle production in response to iron restriction and that these microvesicles contain mycobactin, which can serve as an iron donor and supports replication of iron-starved mycobacteria. Consequently, the results revealed a role of microvesicles in iron acquisition in M. tuberculosis, which can be critical for survival in the host. The production of extracellular vesicles and vesicle-mediated communication is evolutionarily conserved among unicellular and multicellular organisms. Bacteria release membrane vesicles (MVs) containing proteins, genetic material, and lipids as a way to interact with prokaryotic and eukaryotic cells in their environment. Mycobacteria, including Mycobacterium tuberculosis, the causative agent of tuberculosis, release MVs in culture, in macrophages, and in the lungs of infected mice (1). MVs released by M. tuberculosis in culture are packed with immunologically active molecules that can modulate the immune response to the benefit of the bacterium (1). MV production by M. tuberculosis has recently been shown to be under genetic control (2).Environmental factors, including those encountered by pathogens during infection, often influence the production and composition of outer membrane vesicles released by Gram-negative bacteria (3). Iron limitation is a well-recognized hallmark of the host environment. Due to its poor solubility in water in the presence of oxygen and at neutral pH, ferric iron is not found free but rather is sequestered in complexes with host iron binding proteins, such as transferrin, lactoferrin, and ferritin (4). For this reason, and because iron is essential for cell vitality, high-affinity iron acquisition systems are critical for pathogens to proliferate during infection. In fact, competition for iron deeply influences host-pathogen interactions. On one hand, rapid withdrawal of accessible iron is the most prominent example of "nutritional immunity"; on the other hand, iron deficiency in the host is a signal for pathogens to induce the expression of toxins and other virulence factors in conjunction with iron acquisition systems (5). To obtain iron, M. tuberculosis synthesizes and secretes high-affinity iron chelators or siderophores named mycobactins, which are essential for virulence (6, 7). Two forms of mycobactins are produced: carboxymycobactin, an amphiphilic molecule that is secreted into the medium, and mycobactin, a lipophilic molecule that remains cell associated (8). These two siderophores share a core but differ mainly in the length of an alkyl substitution; carboxymycobactin has a short one (2 to 9 carbons), whereas a long one (10 to 21 carbons) chara...

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Disruption of Mycobactin Biosynthesis Leads to Attenuation of Mycobacterium tuberculosis for Growth and Virulence

Abstract: This study highlights the importance of mycobactins in the growth and virulence of M. tuberculosis and establishes the enzymes of mycobactin biosynthesis as novel targets for the development of therapeutic interventions against tuberculosis.

Cited by 111 publications

References 45 publications

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

Role for Mycobacterium tuberculosis Membrane Vesicles in Iron Acquisition

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