Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Jeffrey Buter (First author), Tan-Yun Cheng (First author), Marwan Ghanem, Anita Grootemaat, Xinxin Feng, Sahadevan Raman, Ashmir Plantijn, Thomas Ennis, Joyce Wang, Rachel Cotton, Emilie Layre, Alexandrea Ramnarine, Jacob Mayfield, David Young, Amanda Martinot, Noman Siddiqi, Shoko Wakabayashi, Helena Botella, Roger Calderon, Megan MurraySabine Ehrt, Barry Snider, Michael Reed, Eric Oldfield, Shumin Tan, Eric Rubin, Marcel Behr, Nicole van der Wel, Adriaan Minnaard, Branch Moody

Research output: Contribution to journalArticleAcademicpeer-review


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
Pages (from-to)889–899
JournalNature Chemical Biology
Publication statusPublished - 19 Aug 2019
Externally publishedYes


  • chemical biology
  • immunology
  • tuberculosis
  • organic chemistry
  • analytical chemistry


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