Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent
Mycobacterium abscessus (Mabs) is a rapidly growing Mycobacterium and an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with increased virulence in zebrafish, which involves the formation of massive serpentine cords, abscesses, and rapid larval death. Generating a cord-deficient Mabs mutant would allow us to address the contribution of cording in the physiopathological signs of the R variant. Herein, a deletion mutant of MAB_4780, encoding a dehydratase, distinct from the β-hydroxyacyl-ACP dehydratase HadABC complex, was constructed in the R morphotype. This mutant exhibited an alteration of the mycolic acid composition and a pronounced defect in cording. This correlated with an extremely attenuated phenotype not only in wild-type but also in immunocompromised zebrafish embryos lacking either macrophages or neutrophils. The abolition of granuloma formation in embryos infected with the dehydratase mutant was associated with a failure to replicate in macrophages, presumably due to limited inhibition of the phagolysosomal fusion. Overall, these results indicate that MAB_4780 is required for Mabs to successfully establish acute and lethal infections. Therefore, targeting MAB_4780 may represent an attractive antivirulence strategy to control Mabs infections, refractory to most standard chemotherapeutic interventions. The combination of a dehydratase assay with a high-resolution crystal structure of MAB_4780 opens the way to identify such specific inhibitors.
| Errataetall: |
CommentIn: Nat Rev Microbiol. 2016 Sep;14 (9):545. - PMID 27424941 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:113 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 113(2016), 29 vom: 19. Juli, Seite E4228-37 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Halloum, Iman [VerfasserIn] |
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| Links: |
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| Themen: |
Cording |
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| Anmerkungen: |
Date Completed 27.11.2017 Date Revised 26.07.2023 published: Print-Electronic PDB: 5I7N CommentIn: Nat Rev Microbiol. 2016 Sep;14 (9):545. - PMID 27424941 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1605477113 |
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| Förderinstitution / Projekttitel: |
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NLM262133512 |
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| 245 | 1 | 0 | |a Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent |
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| 500 | |a CommentIn: Nat Rev Microbiol. 2016 Sep;14 (9):545. - PMID 27424941 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Mycobacterium abscessus (Mabs) is a rapidly growing Mycobacterium and an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with increased virulence in zebrafish, which involves the formation of massive serpentine cords, abscesses, and rapid larval death. Generating a cord-deficient Mabs mutant would allow us to address the contribution of cording in the physiopathological signs of the R variant. Herein, a deletion mutant of MAB_4780, encoding a dehydratase, distinct from the β-hydroxyacyl-ACP dehydratase HadABC complex, was constructed in the R morphotype. This mutant exhibited an alteration of the mycolic acid composition and a pronounced defect in cording. This correlated with an extremely attenuated phenotype not only in wild-type but also in immunocompromised zebrafish embryos lacking either macrophages or neutrophils. The abolition of granuloma formation in embryos infected with the dehydratase mutant was associated with a failure to replicate in macrophages, presumably due to limited inhibition of the phagolysosomal fusion. Overall, these results indicate that MAB_4780 is required for Mabs to successfully establish acute and lethal infections. Therefore, targeting MAB_4780 may represent an attractive antivirulence strategy to control Mabs infections, refractory to most standard chemotherapeutic interventions. The combination of a dehydratase assay with a high-resolution crystal structure of MAB_4780 opens the way to identify such specific inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a M. abscessus | |
| 650 | 4 | |a cording | |
| 650 | 4 | |a dehydratase | |
| 650 | 4 | |a virulence | |
| 650 | 4 | |a zebrafish | |
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| 700 | 1 | |a Carrère-Kremer, Séverine |e verfasserin |4 aut | |
| 700 | 1 | |a Blaise, Mickael |e verfasserin |4 aut | |
| 700 | 1 | |a Viljoen, Albertus |e verfasserin |4 aut | |
| 700 | 1 | |a Bernut, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Le Moigne, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Vilchèze, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Guérardel, Yann |e verfasserin |4 aut | |
| 700 | 1 | |a Lutfalla, Georges |e verfasserin |4 aut | |
| 700 | 1 | |a Herrmann, Jean-Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobs, William R |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Kremer, Laurent |e verfasserin |4 aut | |
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