In Vivo Biosynthesis of Terpene Nucleosides Provides Unique Chemical Markers of Mycobacterium tuberculosis Infection. Issue 4 (23rd April 2015)

• Record Type: Journal Article
• Authors: Young, David C.; Layre, Emilie; Pan, Shih-Jung; Tapley, Asa; Adamson, John; Seshadri, Chetan; Wu, Zhongtao; Buter, Jeffrey; Minnaard, Adriaan J.; Coscolla, Mireia; Gagneux, Sebastien; Copin, Richard; Ernst, Joel D.; Bishai, William R.; Snider, Barry B.; Moody, D. Branch
• Is Part Of: Chemistry & biology. Volume 22:Issue 4(2015)
• Page Start: 516
• Page End: 526
• Publication Date: 2015-04-23
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2015.03.015
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N 6 -tuberculosinyladenosine ( N 6 -TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N 6 -TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis. Graphical Abstract: Highlights: N 6 -tuberculosinyladenosine (formed from 1-tuberculosinyladenosine) is described These lipid-linked nucleosides are detected in M. tuberculosis infected mouse lung Abstract : To make better diagnostic tests for tuberculosis, we identified molecules that are abundantly produced by M. tuberculosis within infected mammalian tissues. Two molecules, 1-TbAd and N 6 -TbAd are specifically produced by M. tuberculosis and can be sensitively detected using mass spectrometry, making them attractive targets for clinical test development.