Biochemical characterisation of pivotal enzymes involved in mycobacterial mycolic acid biosynthesis

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 a great need for new and better drugs to treat TB. The work proposed here therefore fulfils the clear need to extend our understanding of the bacterial physiology of the tubercle bacillus in the hope of priming novel therapeutic approaches to this ancient human adversary.

Communication to the general public will be channelled through the University Press Office at Birmingham (http://www.newscentre.bham.ac.uk/office.htm) which has established contacts in the local and national media. The applicants will also highlight there research through personal University based Web pages, which has open access.

Technical Summary

Mycolic acids are essential components of the cell envelope of Mycobacterium tuberculosis and access to comprehensive knowledge of the underlying genetic and biochemical profiles of key enzymes in mycolate synthesis is urgently needed. The following pivotal enzymes, identified in our previous studies will be investigated: (a) the search for an ?alternative? Mt-FabH-like enzyme involved in mycolate biosynthesis and the biochemical/structural characterisation of inhibition of beta-ketoacyl synthase (KAS) enzymes by platensimycin and platensin; (b) determination of the Mt-Pks13 crystal structure, in silico screening for KAS inhibitors and the role of Rv3802c as the mycolyltransferase-II involved in mycolic acid biosynthesis; (c) the role of Mt-MycR in regulation of mycolate biosynthesis; (d) identification and characterisation of other target(s) of the anti-mycobacterial drug isoxyl; and (e) the role of FadB homologues in fatty acid/mycolic acid degradation in M. tuberculosis. Full characterisation of the properties and the role of the above enzymes will be a major advance in mycobacterial cell wall assembly.

Publications

10 25 50
 
Description Programme Grant
Amount £1,778,106 (GBP)
Funding ID MR/K012118/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2013 
End 05/2018
 
Description Research Grant
Amount £404,224 (GBP)
Funding ID G0901690 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2010 
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 MDR TB and problems 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact BBC Inside out

None
Year(s) Of Engagement Activity 2011