In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection

David C Young; Emilie Layre; Shih-Jung Pan; Asa Tapley; John Adamson; Chetan Seshadri; Zhongtao Wu; Jeffrey Buter; Adriaan J Minnaard; Mireia Coscolla; Sebastien Gagneux; Richard Copin; Joel D Ernst; William R Bishai; Barry B Snider; D Branch Moody

doi:10.1016/j.chembiol.2015.03.015

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In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection

Journal article

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Peer reviewed

In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection

David C Young, Emilie Layre, Shih-Jung Pan, Asa Tapley, John Adamson, Chetan Seshadri, Zhongtao Wu, Jeffrey Buter, Adriaan J Minnaard, Mireia Coscolla, …

Chemistry & biology, Vol.22(4), pp.516-526

04/23/2015

DOI: https://doi.org/10.1016/j.chembiol.2015.03.015

PMCID: PMC4432472

PMID: 25910243

Abstract

Nucleosides - chemistry

Magnetic Resonance Spectroscopy

Bacterial Proteins - genetics

Chromatography, High Pressure Liquid

Lipids - biosynthesis

Isomerism

Tuberculosis - diagnosis

Lipids - isolation & purification

Terpenes - chemistry

Animals

Spectrometry, Mass, Electrospray Ionization

Nucleosides - biosynthesis

Bacterial Proteins - metabolism

Lung - metabolism

Mice

Mice, Inbred BALB C

Nucleosides - analysis

Polymorphism, Single Nucleotide

Lipids - analysis

Mycobacterium tuberculosis - metabolism

Mycobacterium tuberculosis - genetics

Biochemistry

Medical Diagnosis

Pathobiology

Tuberculosis

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.

UN Sustainable Development Goals (SDGs)

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Title: In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection; Terpene nucleosides are transformed in vivo and serve as specific chemical markers for M. tuberculosis infection
Creators: David C Young (Author) - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, 1 Jimmy Fund Way, Boston, MA 02115, USA
Emilie Layre (Author) - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, 1 Jimmy Fund Way, Boston, MA 02115, USA
Shih-Jung Pan (Author) - K-RITH, KwuZulu-Natal Research Institute for Tuberculosis & HIV, Nelson R. Mandela School of Medicine-University of Kwazulu-Natal, K-RITH Tower Building, 719 Umbilo Road, Durban, 4001 Private Bag X7, Congela-Durban 4001, South Africa
Asa Tapley (Author) - K-RITH, KwuZulu-Natal Research Institute for Tuberculosis & HIV, Nelson R. Mandela School of Medicine-University of Kwazulu-Natal, K-RITH Tower Building, 719 Umbilo Road, Durban, 4001 Private Bag X7, Congela-Durban 4001, South Africa; UCSF School of Medicine, San Francisco, CA 94143, USA
John Adamson (Author) - K-RITH, KwuZulu-Natal Research Institute for Tuberculosis & HIV, Nelson R. Mandela School of Medicine-University of Kwazulu-Natal, K-RITH Tower Building, 719 Umbilo Road, Durban, 4001 Private Bag X7, Congela-Durban 4001, South Africa; Center for Tuberculosis Research, Division of Infections Diseases, Johns Hopkins University School of Medicine, 1550 Orleans Street Room 108, Baltimore, MD 21231, USA
Chetan Seshadri (Author) - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, 1 Jimmy Fund Way, Boston, MA 02115, USA
Zhongtao Wu (Author) - Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Jeffrey Buter (Author) - Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Adriaan J Minnaard (Author) - Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Mireia Coscolla (Author) - Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland
Sebastien Gagneux (Author) - Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland
Richard Copin (Author) - Division of Infectious Diseases & Immunology, New York University School of Medicine, 522 First Avenue, SRB 901, New York, NY 10016, USA
Joel D Ernst (Author) - Division of Infectious Diseases & Immunology, New York University School of Medicine, 522 First Avenue, SRB 901, New York, NY 10016, USA
William R Bishai (Author) - K-RITH, KwuZulu-Natal Research Institute for Tuberculosis & HIV, Nelson R. Mandela School of Medicine-University of Kwazulu-Natal, K-RITH Tower Building, 719 Umbilo Road, Durban, 4001 Private Bag X7, Congela-Durban 4001, South Africa; Center for Tuberculosis Research, Division of Infections Diseases, Johns Hopkins University School of Medicine, 1550 Orleans Street Room 108, Baltimore, MD 21231, USA
Barry B Snider (Author) - Department of Chemistry MS015, Brandeis University, Waltham, MA 02453-2728, USA
D Branch Moody (Author) - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, 1 Jimmy Fund Way, Boston, MA 02115, USA. Electronic address: bmoody@partners.org
Publication Details: Chemistry & biology, Vol.22(4), pp.516-526
Grant note: U19 AI 111224 / NIAID NIH HHS 1S10RR017269-01 / NCRR NIH HHS R01 AI116604 / NIAID NIH HHS R01 AI 049313 / NIAID NIH HHS U19 AI111224 / NIAID NIH HHS R01 AI090928 / NIAID NIH HHS R01 AI049313 / NIAID NIH HHS U19 AI111211 / NIAID NIH HHS S10 RR017269 / NCRR NIH HHS
Identifiers: 9924012915401921
Academic Unit: Department of Chemistry
Language: English
Resource Type: Journal article

In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection

Abstract

UN Sustainable Development Goals (SDGs)

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