ArticleProceedings of the National Academy of Sciences of the United States of America2014
Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 121 citations in OpenAlex.
- Structure, assembly, and mechanism of the MmpL family of transporters.Microbiology and molecular biology reviews : MMBR · 2026Review
- A requirement formSphere · 2026Article
- Structural elucidation of the hexameric MmpS4-MmpL4 complex frombioRxiv : the preprint server for biology · 2026Article
- Contribution of Proteins to Membrane and Cell Wall Structures in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- Article
- Siderophores and secondary metabolites produced byMicrobiology (Reading, England) · 2025Article
- Structure-Guided Development of a Potent BioA Inhibitor Validates Biotin Synthesis Inhibition as a Therapeutic Strategy for Tuberculosis.bioRxiv : the preprint server for biology · 2025Article
- Verapamil and its metabolite norverapamil inhibit theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis.Nature communications · 2025Article
- The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake.Nature communications · 2025Article
- Mycobactin and clofazimine activity are negatively correlated in mycobacteria.Frontiers in microbiology · 2025Article
- Microbial Siderophores: A New Insight on Healthcare Applications.BME frontiers · 2025Review
- TowardMicroorganisms · 2024Review
- Transcriptomic responses to antibiotic exposure inAntimicrobial agents and chemotherapy · 2024Article
- Article
- The structure of Mycobacterium thermoresistibile MmpS5 reveals a conserved disulfide bond across mycobacteria.Metallomics : integrated biometal science · 2024Article
- In Silico Drug Repurposing Studies for the Discovery of Novel Salicyl-AMP Ligase (MbtA)Inhibitors.Pathogens (Basel, Switzerland) · 2023Article
- TargetingRSC medicinal chemistry · 2023Review
- Intricate link between siderophore secretion and drug efflux inAntimicrobial agents and chemotherapy · 2023Article
- Zinc excess impairsMicrobiology spectrum · 2023Article
14 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.