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Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent.

Abstract：

: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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Halloum I,Carrère-Kremer S,Blaise M,Viljoen A,Bernut A,Le Moigne V,Vilchèze C,Guérardel Y,Lutfalla G,Herrmann JL,Jacobs WR Jr,Kremer L

doi

10.1073/pnas.1605477113

subject

Has Abstract

pub_date

2016-07-19 00:00:00

pages

E4228-37

issue

eissn

0027-8424

issn

1091-6490

pii

1605477113

journal_volume

113

pub_type

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Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent.