MAGPIE Project: The Structure, Biosynthesis and Assembly of the Mycobacterial Cell Envelope

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

Tuberculosis (TB) is a life ?threatening condition that can last for several years during which patients are debilitated and may disseminate the bacterium that causes the disease, Mycobacterium tuberculosis (Mtb). At least 30 million individuals worldwide will have died from TB in the last decade of the 20th century. In the UK the steady decline in TB cases over the whole of the last century halted in the mid 1980s and there has been alarming signs of increased numbers of cases in certain communities. The situation is compounded by the AIDS epidemic and by the emergence of Mtb strains that are resistant to virtually all the drugs that would normally be used to treat TB. It can be argued that, globally, Mtb is the single most important infectious agent affecting mankind. All bacteria have cells that, like plants, are enclosed in a cell wall. This protects the organism from its immediate environment and, fortuitously, presents an important target for drugs, like penicillin, that can be used to treat bacterial infections. However, Mtb has a distinctive cell wall that differs in composition from that of other bacteria; in particular it contains an exceptional amount of unique lipids (fats) and sugars. Although there are drugs that affect the unique Mtb cell wall, the current treatment for tuberculosis lasts 6 months and is potentially toxic to patients who often cease treatment early. Moreover, the efficacy of treatment is threatened by the emergence of drug-resistant strains of Mtb. There is therefore a great need for new and better drugs to treat TB. In this coordinated set of projects, the investigators are combining their particular expertise in analysing the Mtb cell wall to improve our understanding of these remarkable structures and the metabolic processes that are required for their assembly.

Communication to the general public will be channelled through the University Press Office at Birmingham (http://www.newscentre.bham.ac.uk/office.htm) and Leciester (http://www.le.ac.uk/press/), which have established contacts in the local and national media. The MRC Co-operative Group members will also highlight there research through personal University based Web pages, which has open access. This highlights the clinical and research elements of the MRC Co-operative Group.

Technical Summary

The Mycolyl-Arabinogalactan-Peptidoglycan Initiative and Exploitation (MAGPIE) project is aimed at coordinating a continued integrated investigation and exploitation of the basic physiology of the mycolyl-arabinogalactan-peptidoglycan complex and associated free lipids in the cell envelope of Mycobacterium tuberculosis. Mycolic acids are essential envelope components and key drug targets; substantial current progress will be vigorously continued into understanding the enzymology of mycolate synthesis, particularly for condensing and tranferase enzymes. New drugs, targeting mycolate-condensing enzymes, will be synthesized, tested and new analogues developed. Mycolates are supported on an arabinogalactan, linked to the basal wall peptidoglycan; the glycosyltransferases involved in the assembly of this complex matrix will continue to be characterised, as will the related enzymes leading to the prime envelope lipoarabinomannan immunogen. A range of characteristic waxes and antigenic acylated trehalose glycolipids are expressed on the cell surface and the detailed immunology and pathogenic role of these will be unravelled. The expression of cell envelope components in the M. tuberculosis complex, in vivo and in vitro, will be studied, using sensitive methods which will also continue to be applied to the detection of ancient and modern disease. The role of human CD1 recognition systems will be exhaustively explored, revealing innovative directions for the treatment or prevention of tuberculosis. All of the above prime investigations will exploit the full power of modern genomics, as will new areas being developed, such as the role of P450 enzymes, N-acetyl transferases, siderophores and phosphatidylinositol-based lipoglycans from related mycolata taxa.

Publications

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Alderwick LJ (2006) Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis. in Proceedings of the National Academy of Sciences of the United States of America

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Bhowruth V (2007) Synthesis and biological evaluation of a C5-biphenyl thiolactomycin library. in Bioorganic & medicinal chemistry letters

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Bhowruth V (2008) Tuberculosis: a balanced diet of lipids and carbohydrates. in Biochemical Society transactions

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Gratraud P (2008) Antimycobacterial Activity and Mechanism of Action of NAS-91. in Antimicrobial agents and chemotherapy

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Guillonneau C (2009) Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity. in Proceedings of the National Academy of Sciences of the United States of America

 
Description BBSRC Research Grant
Amount £455,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2008 
End 12/2010
 
Description Clinical Research Training Fellowship
Amount £296,000 (GBP)
Funding ID 107302/Z/15/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 09/2018
 
Description MRC Co-operative Group Grant
Amount £330,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2006 
End 01/2011
 
Description MRC Research Grant
Amount £476,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2006 
End 09/2009
 
Description MRc Research Grant
Amount £246,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2009 
End 07/2011
 
Description Newton Fund
Amount £257,854 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2016 
End 12/2018
 
Description Project Grant
Amount £578,141 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2016 
End 11/2019
 
Description Research Grant
Amount £478,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2010 
End 09/2013
 
Description Research Grant
Amount £316,000 (GBP)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2007 
End 02/2011
 
Description Research Grant
Amount £420,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2006 
End 10/2009
 
Description Research Grant
Amount £505,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2010 
End 05/2013
 
Description The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways
Amount £1,720,866 (GBP)
Funding ID MR/S000542/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2019 
End 02/2024
 
Description Wellcome Trust Programme Grant (An integrated multi-disciplinary approach to unravel complex and essential cell wall biosynthetic pathways involved in arabinogalactan and lipoarabinomannan assembly in Mycobacterium tuberculosis)
Amount £1,226,535 (GBP)
Funding ID 081569 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 12/2012
 
Description Wellcome Trust Programme Grant (Novel invariant NKT cell agonists as adjuvants for antigen specific T and B cell responses)
Amount £569,402 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2009 
End 04/2015
 
Title ANALOGS OF ALPHA GALACTOSYLCERAMIDE AND USES THEREOF 
Description There are disclosed compound of formula I, in which R1 represents a hydrophobic moiety adapted to occupy the C' channel of human CDId, R2 represents a hydrophobic moiety adapted to occupy the A' channel of human CDId, such that R1 fills at least at least 30% of the occupied volume of the C' channel compared to the volume occupied by the terminal nC14H29 of the sphingosine chain of a-galactosylceramide when bound to human CDId and R2 fills at least 30% of the occupied volume of the A' channel compared to the volume occupied by the terminal nC25H51 of the acyl chain of a-galactosylceramide when bound to human CDId R3 represents hydrogen or OH, R and R each represent hydrogen and in addition, when R<3> represents hydrogen, R and R together may form a single bond, X represents or -CHA(CHOH)nY or - P(=0)(0<->)0CH2(CH0H)mY, in which Y represents CHB1B2, n represents an integer from 1 to 4, m represents 0 or 1, A årepresents hydrogen, one of B1 and B2 represents H, OH or phenyl, and the other represents hydrogen or one of B1 and B2 represents hydroxyl and the other represents phenyl, in addition, when n represents 4, then A together with one of B1 and B2 together forms a single bond and the other of B1 and B2 represents H, OH or OSO3H and pharmaceutically acceptable salts thereof; the compounds of formula I are indicted for use in the treatment of a virus, microbial infection, parasite, an autoimmune disease, cancer, allergy or asthma 
IP Reference WO2007050668 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact None
 
Title CONJUGATE VACCINES FOR NON-PROTEINACEOUS ANTIGENS 
Description The present invention is directed to pharmaceutical compositions that can be used to immunize subjects using, for example, lipid, glycan, or nucleic acid antigens. These antigens are conjugated to a glycosphingolipid. 
IP Reference WO2007051004 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact None
 
Title galactosyl ceramide derivatives 
Description New derivatives of galactosyl ceramide to promote Th1 responses, and cross-talk between NKT and B cells 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2009
Development Status Actively seeking support
Impact None 
 
Description BBC 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview and presentation on vaccines and new drug targets

None
Year(s) Of Engagement Activity 2007
 
Description BCG Vaccine and problems? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact BBC Inside Out

None
Year(s) Of Engagement Activity 2007
 
Description New TB Drugs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview for BBC Inside Out.

None
Year(s) Of Engagement Activity 2007
 
Description New TB drug targets and vaccines 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An interview with the BBC Inside Out show.

None
Year(s) Of Engagement Activity 2007
 
Description New TB drugs and vaccines? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview with the BBC and Inside Out Show for the West Midlands.

None
Year(s) Of Engagement Activity 2007
 
Description New TB drugs? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview and presentation for the BBC Inside Out

None
Year(s) Of Engagement Activity 2007