The molecular characterisation of the mode of action of the anti-TB agent isoxyl

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.

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 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

Mycolic acids are vital components of the cell envelope of Mycobacterium tuberculosis. Several well-established anti-tuberculosis agents, such as isoniazid and ethionamide, and other agents, such as thiolactomycin and isoxyl, are known to inhibit mycolic acid biosynthesis. In general, isoniazid, ethionamide, and thiolactomycin appear to interfere with biochemical transformations in the elongation cycles, through the inhibition of an enoyl-ACP reductase (InhA) and beta-keto-acyl-ACP synthases (KasA and KasB), which extend the mycolic acid chains. However, the precise mode of action of isoxyl in relation to its inhibitory properties through mycolic acid inhibition is unknown. Recent evidence suggests that isoxyl may be a specific inhibitor of a common step within mycolic acid biosynthesis, such as desaturation or perhaps a dehydratase event. We aim to resolve the mode of action of isoxyl by a concerted application of molecular genetics, combined with the use of specifically tailored inhibitors and detailed product analysis. This approach will allow us to examine the fine detail of the mode of action of isoxyl, and in addition, the precise sequence of events in the anabolic pathway of mycolic acid synthesis to be characterised for the first time. On the broader scale, the gross interrelation of the elongation and desaturation steps in the biosynthetic pathway of mycolic acids has become a point of contention during the past year and these studies will resolve this dilemma. Non-radioactive fluorescent or fluorinated mycolate precursors will be used to unambiguously trace the biosynthetic pathways in detail.

Publications

10 25 50
 
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 £505,280 (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 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