Imperial College London
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DrJulienVaubourgeix

Faculty of Medicine, Department of Infectious Disease

Honorary Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2746j.vaubourgeix Website

 
 
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Location

 

2.42Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ballinger:2019:10.1126/science.aau8959,
author = {Ballinger, E and Mosior, J and Hartman, T and Burns-Huang, K and Gold, B and Morris, R and Goullieux, L and Blanc, I and Vaubourgeix, J and Lagrange, S and Fraisse, L and Sans, S and Couturier, C and Bacque, E and Rhee, K and Scarry, SM and Aube, J and Yang, G and Ouerfelli, O and Schnappinger, D and Ioerger, TR and Engelhart, CA and McConnell, JA and McAulay, K and Fay, A and Roubert, C and Sacchettini, J and Nathan, C},
doi = {10.1126/science.aau8959},
journal = {Science},
title = {Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition},
url = {http://dx.doi.org/10.1126/science.aau8959},
volume = {363},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - INTRODUCTIONMycobacterium tuberculosis (Mtb) is the leading global cause of lethal infection in humans and accounts for the largest number of drug-resistant infections by a single bacterial pathogen. Resistance is particularly high against the most widely prescribed tuberculosis (TB) drug, isoniazid. Isoniazid blocks synthesis of mycolates, ultralong-chain fatty acids that provide structure to the waxy coat that surrounds Mtb cells and are incorporated into some of its virulence lipids. There is currently no known method to block the synthesis of both mycolates and nonmycolate-containing virulence lipids of Mtb at a single point of control. One such control point is phosphopantetheinyl transferase (PptT). PptT transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to acyl carrier proteins (ACPs) that synthesize the lipids critical to Mtb structural integrity and virulence.RATIONALETB drug discovery often begins with whole-cell, high-throughput screens that yield compounds that kill Mtb by unknown means. Selection of Mtb mutants resistant to these compounds can indicate candidate targets of the active compound, but experimental validation is required to confirm the functionally relevant target, which is often an enzyme. A suitable target must be essential in vivo, such that its inhibition precludes development of TB in animal models, but also “vulnerable,” meaning that a pharmacologically attainable level of inhibition should be lethal to Mtb within a patient. The inhibitor should act only on Mtb, and resistance should be rare.RESULTSScreening a chemical library revealed an amidino-urea compound called “8918” that kills Mtb, including drug-resistant clinical isolates. 8918 inhibits Mtb in mice and spares other bacteria, yeast, and mammalian cells.Rare Mtb mutants resistant to 8918 bore a point mutation in the PptT gene rv2794c, altering an amino acid residue overlying the Ppt-binding pocket of PptT. When Mtb carried the mutant allel
AU  - Ballinger,E
AU  - Mosior,J
AU  - Hartman,T
AU  - Burns-Huang,K
AU  - Gold,B
AU  - Morris,R
AU  - Goullieux,L
AU  - Blanc,I
AU  - Vaubourgeix,J
AU  - Lagrange,S
AU  - Fraisse,L
AU  - Sans,S
AU  - Couturier,C
AU  - Bacque,E
AU  - Rhee,K
AU  - Scarry,SM
AU  - Aube,J
AU  - Yang,G
AU  - Ouerfelli,O
AU  - Schnappinger,D
AU  - Ioerger,TR
AU  - Engelhart,CA
AU  - McConnell,JA
AU  - McAulay,K
AU  - Fay,A
AU  - Roubert,C
AU  - Sacchettini,J
AU  - Nathan,C
DO  - 10.1126/science.aau8959
PY  - 2019///
SN  - 0036-8075
TI  - Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition
T2  - Science
UR  - http://dx.doi.org/10.1126/science.aau8959
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000457409400042&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/69306
VL  - 363
ER  -
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