Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Jeffrey Buter, Tan Yun Cheng, Marwan Ghanem, Anita E. Grootemaat, Sahadevan Raman, Xinxin Feng, Ashmir R. Plantijn, Thomas Ennis, Joyce Wang, Rachel N. Cotton, Emilie Layre, Alexandrea K. Ramnarine, Jacob A. Mayfield, David C. Young, Amanda Jezek Martinot, Noman Siddiqi, Shoko Wakabayashi, Helene Botella, Roger Calderon, Megan MurraySabine Ehrt, Barry B. Snider, Michael B. Reed, Eric Oldfield, Shumin Tan, Eric J. Rubin, Marcel A. Behr, Nicole N. van der Wel, Adriaan J. Minnaard, D. Branch Moody

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)889-899
Number of pages11
JournalNature chemical biology
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2019

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Buter, J., Cheng, T. Y., Ghanem, M., Grootemaat, A. E., Raman, S., Feng, X., Plantijn, A. R., Ennis, T., Wang, J., Cotton, R. N., Layre, E., Ramnarine, A. K., Mayfield, J. A., Young, D. C., Jezek Martinot, A., Siddiqi, N., Wakabayashi, S., Botella, H., Calderon, R., ... Moody, D. B. (2019). Mycobacterium tuberculosis releases an antacid that remodels phagosomes. Nature chemical biology, 15(9), 889-899. https://doi.org/10.1038/s41589-019-0336-0