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The mode of fosmidomycin resistance in Mycobacterium tuberculosis

Reference	BB/D000181/1
Principal Investigator / Supervisor	Professor Tanya Parish
Co-Investigators / Co-Supervisors	Dr Amanda Brown
Institution	Queen Mary University of London
Department	Sch of Medicine & Dentistry
Funding type	Research
Value (£)	289,742
Status	Completed
Type	Research Grant
Start date	08/12/2005
End date	07/12/2008
Duration	36 months

Abstract

The treatment of mycobacterial infections with antibiotics is notoriously problematic. For example, anti-tuberculosis therapy involves combinations of several antimicrobial agents administered over 6-9 months and there are no available treatments for certain other infections. Antibiotic resistance is also on the rise in Mycobacterium tuberculosis isolates. Thus there is an urgent need for new or improved antibiotics. Unravelling the mechanism of resistance to current antibiotics may lead to the development of improved treatments. Isoprenoids are an essential requirement of all living organisms and can be synthesised by two independent pathways - the mevalonate pathway found in most organisms and the non-mevalonate or DOXP pathway found in some bacteria and the plastids of algae and higher plants. The antibiotic fosmidomycin targets the DOXP pathway by inhibiting Dxr, the DOXP reductoisomerase. Mycobacteria only possess this pathway and therefore the genes encoding the enzymes should be essential for viability. A single dxr homologue has been identified in the Mycobacterium tuberculosis genome and the encoded protein is sensitive to inhibition by fosmidomycin. However, mycobacteria are resistant to fosmidomycin and the dxr gene is predicted to be non-essential. Three explanations for this apparent contradiction can be proposed (1) there is an otherwise unannotated gene which encodes an enzyme having the same function as Dxr (2) there is an alternative novel pathway of isoprenoid biosynthesis or (3) that Dxr is the sole DOXP reductoisomerase, the non-essentiality data is a false prediction and that fosmidomycin resistance is due to other factors, for example lack of transport into the cell. The aim of this project is to determine which of these scenarios is correct. We will determine whether resistance to fosmidomycin is due to redundancy in the DOXP pathway or results from other factors such as lack of permeation. We will address this central question of fosmidomycin resistance by (1) determining if dxr is essential in Mycobacterium tuberculosis (2) determining if other DOXP pathway genes are essential in Mycobacterium tuberculosis (3) determining whether fosmidomycin resistance is due to a lack of uptake (4) determining the key residues for Dxr activity

Summary

Mycobacteria are the cause of major disease and mortality in both man and animals. The emergence of multi-drug resistant strains poses a serious threat to our ability to treat these potentially fatal diseases. Many common antibiotics are not active against mycobacteria and so the panel of available agents for treatment is small. Thus the search for new anti-mycobacterial agents is an urgent priority. As well as identifying novel agents, existing antibiotics can be modified to be active against mycobacteria. In order to do this, we need to understand why the bacteria are resistant in the first place. The aim of this project is to investigate why the bacteria that cause tuberculosis are resistant to the antibiotic fosmidomycin using modern molecular approaches. An understanding of this may lead in future to the development of new effective antibiotics. The project will be carried out at Barts and the London, Queen Mary's School of Medicine and Dentistry in the East End of London. Studies on tuberculosis are particularly relevant to this area where rates of infection are the highest in the country.

Committee	Closed Committee - Plant & Microbial Sciences (PMS)
Research Topics	Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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