Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis
Open accessAbstract
Iron is an essential nutrient for most bacterial pathogens, but is restricted by the host immune system. Mycobacterium tuberculosis (Mtb) utilizes two classes of small molecules, mycobactins and carboxymycobactins, to capture iron from the human host. Here, we show that an Mtb mutant lacking the mmpS4 and mmpS5 genes did not grow under low iron conditions. A cytoplasmic iron reporter indicated that the double mutant experienced iron starvation even under high-iron conditions. Loss of mmpS4 and mmpS5 did not change uptake of carboxymycobactin by Mtb. Thin layer chromatography showed that the ΔmmpS4/S5 mutant was strongly impaired in biosynthesis and secretion of siderophores. Pull-down experiments with purified proteins demonstrated that MmpS4 binds to a periplasmic loop of the associated transporter protein MmpL4. This interaction was corroborated by genetic experiments. While MmpS5 interacted only with MmpL5, MmpS4 interacted with both MmpL4 and MmpL5. These results identified MmpS4/MmpL4 and MmpS5/MmpL5 as siderophore export systems in Mtb and revealed that the MmpL proteins transport small molecules other than lipids. MmpS4 and MmpS5 resemble periplasmic adapter proteins of tripartite efflux pumps of Gram-negative bacteria, however, they are not only required for export but also for efficient siderophore synthesis. Membrane association of MbtG suggests a link between siderophore synthesis and transport. The structure of the soluble domain of MmpS4 (residues 52-140) was solved by NMR and indicates that mycobacterial MmpS proteins constitute a novel class of transport accessory proteins. The bacterial burden of the mmpS4/S5 deletion mutant in mouse lungs was lower by 10,000-fold and none of the infected mice died within 180 days compared to wild-type Mtb. This is the strongest attenuation observed so far for Mtb mutants lacking genes involved in iron utilization. In conclusion, this study identified the first components of novel siderophore export systems which are essential for virulence of Mtb.
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M. tuberculosis mechanisms for iron uptake include a heme transporter and two classes of siderophores, mycobactins and carboxymycobactins.
“Its mechanisms for iron uptake include a heme transporter and two classes of siderophores, mycobactins and carboxymycobactins (Mitra et al., 2019;Wells et al., 2013).”
From Iron in infection and immunity (2020) · cites this paper as Wells et al., 2013
The Introduction identifies mycobactin and carboxymycobactin as siderophores used by M. tuberculosis to acquire iron. The Results also show that hemin can serve as an alternative iron source, but our copy does not identify a heme transporter; the heme-acquisition study appears only in the References. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGenetic mutations affecting siderophore utilization by bacteria resulted in significant reduction in bacterial virulence or bacterial numbers in the lung and absent mortality in mice with tuberculosis.
“Genetic mutations affecting siderophore utilization by the bacteria resulted in significant reduction in bacterial virulence or bacterial numbers in the lung and absent mortality in mice with tuberculosis (207, 208).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [207]
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- Authors
- Wells, R. M., Jones, C. M., Xi, Z., Speer, A., Danilchanka, O., Doornbos, K. S., Sun, P., Wu, F., Tian, C., & Niederweis, M.
- Affiliations
- University of Alabama at Birmingham (US)
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Niederweis, Michael
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-01-31
- Volume
- 9
- Issue
- 1
- Pages
- e1003120
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3561183
- OpenAlex
- W2028862917
- Cited by
- 267
- References
- 51
- Citations by year
- 2026: 18 · 2025: 30 · 2024: 14 · 2023: 22 · 2022: 17 · 2021: 19 · 2020: 22 · 2019: 9 · 2018: 22 · 2017: 20 · 2016: 17 · 2015: 23 · 2014: 22 · 2013: 11
- FWCI
- 17.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Colorado State University
- National Institutes of Health (HHSN266200400091C, AI074805)
- National Institute of General Medical Sciences (T32GM008361)
- National Institute of Allergy and Infectious Diseases (AI074805, T32AI007493, P01AI074805, T32AI007041, HHSN272201000015I, R01AI083632, HHSN 266200400091C, AI-07041, AI083632)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- Mycobacterium tuberculosis, mycobactin, iron acquisition, iron starvation, virulence, tripartite efflux pump, NMR structure, mouse lung infection, bacterial attenuation
- MeSH terms
- Animals, Bacterial Outer Membrane Proteins, Bacterial Proteins, Carrier Proteins, Chromatography, Thin Layer, Female, Iron, Lung, Mice, Inbred BALB C, Mycobacterium tuberculosis, Oxazoles, Receptors, Cell Surface, Spleen, Tuberculosis, Virulence, Survival Rate, Siderophores, Sequence Deletion, Protein Structure, Tertiary, Mice, Host-Pathogen Interactions
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