TY - JOUR
T1 - In vivo biosynthesis of terpene nucleosides provides unique chemical markers of mycobacterium tuberculosis infection
AU - Young, David C.
AU - Layre, Emilie
AU - Pan, Shih Jung
AU - Tapley, Asa
AU - Adamson, John
AU - Seshadri, Chetan
AU - Wu, Zhongtao
AU - Buter, Jeffrey
AU - Minnaard, Adriaan J.
AU - Coscolla, Mireia
AU - Gagneux, Sebastien
AU - Copin, Richard
AU - Ernst, Joel D.
AU - Bishai, William R.
AU - Snider, Barry B.
AU - Moody, D. Branch
N1 - Funding Information:
The authors thank Lisa Prach and Thomas Alber for providing Rv3378c enzyme and Thomas Ennis for a BLAST search result. This work was funded by Mark and Lisa Schwartz , the Burroughs Wellcome Fund Program in Translational Medicine , the TB Vaccine Accelerator Award from the Bill and Melinda Gates Foundation and the NIAID ( U19 AI 111224 , R01 049313 ), and the Dutch Science Foundation NWO . The 800 MHz spectrometer in the Landsman Research Facility, Brandeis University, was purchased under the NIH RR High-End Instrumentation program , 1S10RR017269-01 .
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/4/23
Y1 - 2015/4/23
N2 - 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, N6-tuberculosinyladenosine (N6-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N6-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.
AB - 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, N6-tuberculosinyladenosine (N6-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N6-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.
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U2 - 10.1016/j.chembiol.2015.03.015
DO - 10.1016/j.chembiol.2015.03.015
M3 - Article
C2 - 25910243
AN - SCOPUS:84928398396
VL - 22
SP - 516
EP - 526
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 4
ER -