5i7n

Publication Abstract from PubMed

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 beta-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.

Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent.,Halloum I, Carrere-Kremer S, Blaise M, Viljoen A, Bernut A, Le Moigne V, Vilcheze C, Guerardel Y, Lutfalla G, Herrmann JL, Jacobs WR Jr, Kremer L Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):E4228-37. doi:, 10.1073/pnas.1605477113. Epub 2016 Jul 6. PMID:27385830^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.