Member SpotlightsDrug Discovery Targets for Mycobacterium tuberculosis Tanya Parish, Ph.D. A Science Advisory Board Member since 1998.  Parish in Torridon, Scotland during her honeymoon. Tanya Parish, Ph.D., is a Professor of Mycobacteriology at the University of London, UK, and also a Principal Investigator for the Infectious Disease Research Institute (IDRI), US. She received her Ph.D. in mycobacterial genetics from the National Institute of Medical Research, UK, and her studies with Mycobacterium tuberculosis began with her post-doctoral and Lecturer position at the London School for Hygiene & Tropical Medicine. In 2000, she moved to Barts and the London (BL) Medical School to set up her own research project on the biology and pathogenicity of M. tuberculosis. In 2007, Parish took on a second position as a PI for IDRI. She is a member of the Society for General Microbiology, UK, American Society for Microbiology, and the Acid Fast Club, UK, a society for those interested in mycobacteria. In her leisure time, Parish follows football (soccer) and supports Torquay United, Arsenal, and England. She's followed the England International team across the globe. She also enjoys trips to vineyards in different parts of the world. Research Interests My area of interest is in the biology of M. tuberculosis. I currently hold two positions: as Professor of Mycobacteriology in London and Senior Scientist/PI in Seattle. My focus has shifted from the purely academic into applied fields. I currently run two research groups with complementary and interlinked aims. In London (BL), my academic research focuses on understanding the biology and pathogenic strategies of the extremely successful global human pathogen, M. tuberculosis. As part of our work, we are looking at the basic biology of several metabolic pathways, as well as the regulatory mechanisms that M. tuberculosis utilizes to control their activity in response to the environment. In Seattle (IDRI), my work focuses on target identification and validation for early stage drug discovery efforts against tuberculosis. In partnership with other groups within IDRI, we aim to progress these into full drug discovery efforts. Underpinning both efforts, we are developing novel genetic techniques, which can be applied to M. tuberculosis. One of our main aims is to improve methods for confirming target essentiality and vulnerability with M. tuberculosis. I have always been interested in microorganisms and gene regulation since my first degree. I graduated into looking at gene regulation in M. tuberculosis and became fascinated by the complexity of the pathogenic strategies of these bacteria. At the same time, I became aware of the terrible toll that tuberculosis takes on the global population, especially in the developing world. The fact that we desperately need new drugs and/or vaccines to combat this killer motivates me to continue to conduct basic and applied research, despite the technical difficulties. Career Expectations Until recently, my career seemed to take a logical and simple direction, following a traditional academic path from student to professor and my focus was purely on conducting basic research. Last year saw a big change in my direction, having taken the decision to split my time between two groups, one on each side of the Atlantic--in the process, earning myself a transatlantic commute and research meetings in the middle of the night. However, setting up a group within a not-for-profit organization whose aim is to produce new therapeutics does bring immense benefits. Perhaps most importantly, by our ability to transfer and apply the knowledge we gain from biology directly into drug discovery efforts and taking our discoveries further than we could within a purely academic environment. I would like to see our efforts in technique development and target identification come to fruition and be successfully applied. Ultimately the aim is to see novel anti-TB compounds being used to reduce global suffering. The following questions are specific to our current Spotlight on Drug Discovery: In what way does your position contribute to the drug discovery pipeline? Our work is focused on identifying important metabolic pathways (and regulatory mechanisms), which will provide good targets for inhibition during infection. Once identified, we use genetic methods to validate the target. For M. tuberculosis, this means conducting a lengthy procedure to determine if the gene is essential under in vitro (culture) conditions, or under specific conditions which mimic infection. The next stage is to confirm that the target is required in vivo, by constructing conditional mutants, in which we can control the level of the target being expressed. Are your drug discovery efforts physiology-based, target-based, or do they utilize a combination of the two? We aim to identify and validate our target first. Targets may be identified by many different approaches, so depending on our current knowledge, we need to further validate them with genetic or chemical approaches. The aim is to use a target-based approach, but to deliver this in the context of the physiology of the organism; for example, by using target-based whole cell screening approaches. What disease mechanisms are particular to the drug candidate compounds that you work with? We are looking at developing drugs to eradicate tuberculosis, caused by M. tuberculosis. Current estimates are that nearly 2 million people die from tuberculosis each year. M. tuberculosis can also cause latent infections which last for decades before reactivation. Current TB treatments are lengthy and involve mutliple antibiotics; in addition there is an increase in resistant strains, so new and better antibiotics are needed. In particular we are looking for compounds which have the potential to shorten therapy. Are your compounds designed to target receptors, proteins/enzymes, DNA, or RNA/ribosomal targets & how would you rate their efficiency in reaching those targets? The majority of our targets are enzymes/proteins involved in basic metabolic or pathogenic processes. The major problem is getting the compound into the bacterial cell. For a number of current antibiotics, it is clear that they are ineffective against M. tuberculosis for precisely the reason that they cannot access the susceptible intracellular target and are excluded by the hydrophobic cell wall. In addition, M. tuberculosis is an intracellular pathogen, which means that in practice the compound must also be able to penetrate eukaryotic cells. After initial discovery, what methods are used to validate the target before assay development? Target validation usually starts with an assessment of the essentiality of the gene under standard growth conditions in culture medium. If non-essential, we profile deletion strains using various growth models which mimic aspects of infection and finally use an in vivo model of infection. If essential, we attempt to construct conditional mutants which can be used for screening in vivo. At the same time, we determine the vulnerability of the target by down regulating expression to determine the minimum amount of protein the cells could survive with. What technology or knowledge limitations can contribute to the high failure rate of compound screening? For bacterial enzymes, there has been a low rate of success in identifying inhibitory compounds. For M. tuberculosis there are additional challenges, since the organism itself can be quite impermeable, owing to its lipid-rich cell wall and thus many inhibitors coming out of traditional enzyme-based screens are ineffective against the whole cell, due to lack of penetration. In contrast whole cell screens are technically challenging when working with a respiratory pathogen, which infects via aerosols, under Biosafety Level 3 conditions. How do you predict increased efficiencies in genomics technologies will contribute to the progress of drug discovery? The genome of M. tuberculosis has been available for a number of years. However, we still do not know the function of a large proportion of the encoded proteins. Large-scale mutagenesis studies have already revolutionized our ability to predict which genes are required in any given environment. In the future, the possibility of conducting large-scale gene knockdown (or conditional mutagenesis) will have a similarly large effect on our ability to predict which targets are vulnerable to inhibition. What short or long-term effects will a demand for a higher compound success rate have on drug discovery companies? The antimicrobial field has seen a withdrawal of investment by large pharmaceutical companies. However, a number of smaller entities and alternative funding mechanisms provide some promise for the future, at least in terms of developing new agents against some of the largest global scourges, such as M. tuberculosis. To discuss drug discovery and other topics with fellow Science Advisory Board members, please visit our community forum. Web Links Barts & the London Medical School IDRI (Infectious Disease Research Institute) Publications A.G. Amin, R. Goude, L. Shi, J. Zhang, D. Chatterjee and T. Parish. EmbA is an essential arabinosyltransferase in Mycobacterium tuberculosis. 2008. Microbiology. 154: 226-239. H. Eoh, A.C. Brown, L. Buetow, W.N. Hunter, T. Parish, D. Kaur, P.J. Brennan, and D.C. Crick. Characterization of the Mycobacterium tuberculosis 4–diphosphocytidyl–2–C–methyl–D–erythritol synthase: potential for drug development. 2007. J. Bacteriol. 189: 8922-8927. E. Sacco, A.S. Covarrubias, H.M. O'Hare, P. Carroll, N. Eynard, T.A. Jones, T. Parish, M. Daffé, K. Bäckbro, A. Quémard. 2007. The missing piece of the type II fatty acid synthase system from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA. 104: 14628-14633. D. Robertson, P. Carroll and T. Parish. 2007. Rapid recombination screening to test gene essentiality demonstrates that pyrH is essential in Mycobacterium tuberculosis. Tuberculosis. 87: 450-458. P. Carroll, A. C. Brown, A. Hartridge and T. Parish. 2007. Expression of Mycobacterium tuberculosis Rv1991c using an arabinose-inducible promoter demonstrates its role as a toxin. FEMS Microbiol. Lett. 274: 73-82. P. Carroll, D.G.N. Muttucumuaru and T. Parish. Use of a tetracycline-inducible system for conditional expression in Mycbacterium tuberculosis and Mycobacterium smegmatis. 2005. Appl. Env. Microbiol. 71: 3077 -3084. T. Parish, M. Schaeffer, G. Roberts and K. Duncan. HemZ is essential for the growth of Mycobacterium tuberculosis. 2005. Tuberculosis.85: 197-204. T. Parish. 2003. Starvation survival response of Mycobacterium tuberculosis. J. Bacteriol. 185: 6702-6706. T. Parish, D.A. Smith, G. Roberts, J. Betts and N.G. Stoker. 2003. The senX3-regX3 two component regulatory system of Mycobacterium tuberculosis is required for virulence. Microbiol. 149: 1423-1435. ### << Previous Next >> [ View All Member Spotlights ] |
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