MRC National Institute for Medical Research, London
Science for Health
Douglas Young group project:
Gene expression and pathogenicity in mycobacteria - Roger Buxton
We are investigating some of the regulatory systems that M. tuberculosis uses to control its gene expression in order to define new drug targets, concentrating on systems that appear to be unique to, or characteristic of, M. tuberculosis.
The cyclic AMP receptor protein (CRP) is the archetypical example of a global regulatory system, responding to the second messenger cAMP to act as a transcriptional activator. M. tuberculosis synthesizes large amounts of cAMP, and levels rise after infection of macrophages. In collaboration with Jeff Green (University of Sheffield) we have shown that CRP is required for a successful virulent infection and that it controls genes coding for the secretion of the major antigens ESAT-6 and CFP-10 required for such an infection, and also genes coding for functions required for entry into, and exit from, the persistent state. One gene in particular, whiB1, codes for a protein containing a nitric oxide iron-sulphur cluster. Nitric oxide is implicated in macrophage-induced killing of M. tuberculosis and entry into the persistent state. We are investigating how the WhiB1 protein may integrate the transcriptional response to cAMP and NO.
Another gene regulatory system seemingly characteristic of mycobacteria is the serine-threonine protein kinases (STPKs) originally thought to be restricted to higher organisms. In collaboration with Steve Smerdon (Division of Molecular Structure), we are investigating some of these STPKs and the interactions that they make with proteins containing the fork-head associated (FHA) modular phosphopeptide recognition domain. One of these FHA-containing proteins, controlled by phosphorylation mediated by an STPK, codes for an ABC transporter protein; this protein is required for a successful infection by M. tuberculosis. Another STPK involved in regulating glutamate metabolism is essential for bacterial growth and is thus a potential drug target. Together with colleagues at MRC-Technology we have been running high throughput drug screens for inhibitors of STPKs.
Selected publications
- Smith L, Stapleton MR, Fullstone GJM, Crack JC, Thomson AJ, Le Brun NE, Hunt DM, Harvey E, Adinolfi S, Buxton RS and Green J (2010)
Mycobacterium tuberculosis WhiB1 is an essential DNA-binding protein with a nitric oxide-sensitive iron-sulphur cluster.
Biochemical Journal Epub ahead of print, PubMed abstract - Stapleton M, Haq I, Hunt DM, Arnvig KB, Artymiuk PJ, Buxton RS and Green J (2010)
Mycobacterium tuberculosis cAMP receptor protein (Rv3676) differs from the Escherichia coli paradigm in its cAMP binding and DNA binding properties and transcription activation properties.
Journal of Biological Chemistry 285, 7016-7027 PubMed abstract - Lougheed KEA, Taylor DL, Osborne SA, Bryans JS and Buxton RS (2009)
New anti-tuberculosis agents amongst known drugs.
Tuberculosis 89, 364-370 PubMed abstract - Hunt DM, Saldanha JW, Brennan JF, Benjamin P, Strom M, Cole JA, Spreadbury CL and Buxton RS (2008)
Single nucleotide polymorphisms that cause structural changes in the cyclic AMP receptor protein transcriptional regulator of the tuberculosis vaccine strain Mycobacterium bovis BCG alter global gene expression without attenuating growth.
Infection and Immunity 76, 2227-2234 PubMed abstract - Rickman L, Scott C, Hunt DM, Hutchinson T, Menéndez MC, Whalan R, Hinds J, Colston MJ, Green J and Buxton RS (2005)
A member of the cAMP receptor protein family of transcription regulators in Mycobacterium tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for a resuscitation promoting factor.
Molecular Microbiology 56, 1274-1286 PubMed abstract - Curry JM, Whalan R, Hunt DM, Gohil K, Strom M, Rickman L, Colston MJ, Smerdon SJ and Buxton RS (2005)
An ABC transporter containing a forkhead-associated domain interacts with a serine-threonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice.
Infection and Immunity 73, 4471-4477 PubMed abstract
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- Gene expression and pathogenicity in mycobacteria - Roger Buxton
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