Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis
Abstract To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are required for mycobactin secretion and drug efflux. In clinical strains, overproduction of MmpL5 co...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56888-6 |
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| author | Jennifer C. Earp Alisa A. Garaeva Virginia Meikle Michael Niederweis Markus A. Seeger |
| author_facet | Jennifer C. Earp Alisa A. Garaeva Virginia Meikle Michael Niederweis Markus A. Seeger |
| author_sort | Jennifer C. Earp |
| collection | DOAJ |
| description | Abstract To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are required for mycobactin secretion and drug efflux. In clinical strains, overproduction of MmpL5 confers resistance towards bedaquiline and clofazimine, key drugs to combat multidrug resistant tuberculosis. Here, we present cryogenic-electron microscopy structures of MmpL4 and identify a mycobactin binding site, which is accessible from the cytosol and also required for bedaquiline efflux. An unusual coiled-coil domain predicted to extend 130 Å into the periplasm is essential for mycobactin and bedaquiline efflux by MmpL4 and MmpL5. The mycobacterial acyl carrier protein MbtL forms a complex with MmpL4, indicating that mycobactin synthesis and export are coupled. Thus, MmpL4 and MmpL5 constitute the core components of a unique multi-subunit machinery required for iron acquisition and drug efflux by M. tuberculosis. |
| format | Article |
| id | doaj-art-a3e5416cc44b4b2d8b5bbbe753a5308e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a3e5416cc44b4b2d8b5bbbe753a5308e2025-08-20T02:59:35ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-56888-6Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosisJennifer C. Earp0Alisa A. Garaeva1Virginia Meikle2Michael Niederweis3Markus A. Seeger4Institute of Medical Microbiology, University of ZurichInstitute of Medical Microbiology, University of ZurichDepartment of Microbiology, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamInstitute of Medical Microbiology, University of ZurichAbstract To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are required for mycobactin secretion and drug efflux. In clinical strains, overproduction of MmpL5 confers resistance towards bedaquiline and clofazimine, key drugs to combat multidrug resistant tuberculosis. Here, we present cryogenic-electron microscopy structures of MmpL4 and identify a mycobactin binding site, which is accessible from the cytosol and also required for bedaquiline efflux. An unusual coiled-coil domain predicted to extend 130 Å into the periplasm is essential for mycobactin and bedaquiline efflux by MmpL4 and MmpL5. The mycobacterial acyl carrier protein MbtL forms a complex with MmpL4, indicating that mycobactin synthesis and export are coupled. Thus, MmpL4 and MmpL5 constitute the core components of a unique multi-subunit machinery required for iron acquisition and drug efflux by M. tuberculosis.https://doi.org/10.1038/s41467-025-56888-6 |
| spellingShingle | Jennifer C. Earp Alisa A. Garaeva Virginia Meikle Michael Niederweis Markus A. Seeger Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis Nature Communications |
| title | Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis |
| title_full | Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis |
| title_fullStr | Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis |
| title_full_unstemmed | Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis |
| title_short | Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis |
| title_sort | structural basis of siderophore export and drug efflux by mycobacterium tuberculosis |
| url | https://doi.org/10.1038/s41467-025-56888-6 |
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