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Mycobacterium tuberculosis releases an antacid that remodels phagosomes.

TitleMycobacterium tuberculosis releases an antacid that remodels phagosomes.
Publication TypeJournal Article
Year of Publication2019
AuthorsButer J, Cheng T-Y, Ghanem M, Grootemaat AE, Raman S, Feng X, Plantijn AR, Ennis T, Wang J, Cotton RN, Layre E, Ramnarine AK, Mayfield JA, Young DC, Martinot AJezek, Siddiqi N, Wakabayashi S, Botella H, Calderon R, Murray M, Ehrt S, Snider BB, Reed MB, Oldfield E, Tan S, Rubin EJ, Behr MA, van der Wel NN, Minnaard AJ, D Moody B
JournalNat Chem Biol
Volume15
Issue9
Pagination889-899
Date Published2019 09
ISSN1552-4469
KeywordsAnimals, Antacids, Gene Expression Regulation, Bacterial, Humans, Hydrogen-Ion Concentration, Lipids, Lysosomes, Macrophages, Mice, Molecular Structure, Mycobacterium kansasii, Mycobacterium tuberculosis, Phagosomes, Prevalence
Abstract

Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C20 lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.

DOI10.1038/s41589-019-0336-0
Alternate JournalNat Chem Biol
PubMed ID31427817
PubMed Central IDPMC6896213
Grant ListK08 AI135098 / AI / NIAID NIH HHS / United States
R01 AI116604 / AI / NIAID NIH HHS / United States
U19 AI111224 / AI / NIAID NIH HHS / United States

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