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Our research is using a targeted structural and functional approach to understanding at the molecular level how bacteria cause disease. We have focused our efforts in the main part on bacterial pathogens that continue to pose a significant health risk to the very young and elderly and have identified a number of vital processes within these pathogens to characterize and assess as targets for drug discovery. Our interests lie predominately in understanding the mechanisms used by bacterial pathogens to adhere to the host cell surfaces and the regulation of virulence. Presently we have several projects focused on understanding specific processes important to bacterial pathogenesis in three important human pathogens Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa:
Streptococcus pneumoniae is the most common cause of bacterial meningitis, community-acquired pneumonia, bacteremia and otitis media worldwide. Prevention and treatment of pneumococcal disease remains challenging due to limited availability of an effective vaccine for children, emergence of antibiotic resistance and the difficulties in detecting the many types of infection the pneumococcus causes. The image on the right illustrates some of our recent work where we determined the structure of oseltamivir carboxylate (Tamiflu) bound at the active site of neuraminidase A (nanA) of S. pneumoniae
Non-typeable Haemophilus influenzae (NTHI) is a benign nasopharyngeal commensal microorganism, but also an opportunistic invader of the normally sterile middle ear space. As such, NTHI predominates in both chronic otitis media(OM). As forStreptococcus pneumoniae NTHI strains principally have a role in other localized respiratory diseases such as acute sinusitis, community-acquired pneumonia and have important consequences in patients with chronic obstructive pulmonary diseases and cystic fibrosis.
Pseudomonas aeruginosa is an opportunistic, nosocomial pathogen that typically infects the pulmonary and urinary tract and a variety of systemic infections, particularly in patients with severe burns and patients who are immunosuppressed. In addition cystic fibrosis patients are characteristically susceptible to chronic infection by P. aeruginosa. It is the most common pathogen isolated from short-stay hospitalized patients and due to the emergence of multi-drug resistance strains has become a significant public health problem.
Crystals of a virulence factor from NTHI
Identification and validation of potential targets for the development of novel antimicrobials to combat the emergence of multidrug resistance strains of these pathogens is the ultimate aim of the research.
1. Gut, H., Xu, G., Taylor, G. L., and Walsh, M. A. (2011) Structural Basis for Streptococcus pneumoniae NanA Inhibition by Influenza Antivirals Zanamivir and Oseltamivir Carboxylate, Journal of molecular biology 409, 496-503.
2. Delagenière, S., Brenchereau, P., Launer, L., Ashton, A. W., Leal, R., Veyrier, S., Gabadinho, J., Gordon, E. J., Jones, S. D., Levik, K. E., McSweeney, S. M., Monaco, S., Nanao, M., Spruce, D., Svensson, O., Walsh, M. A., and Leonard, G. A. (2011) ISPyB: an information management system for synchrotron macromolecular crystallography, Bioinformatics 27, 3186-3192.
3. Cheng, Z., He, Y. W., Lim, S. C., Qamra, R., Walsh, M. A., Zhang, L. H., and Song, H. (2010) Structural basis of the sensor-synthase interaction in autoinduction of the quorum sensing signal DSF biosynthesis, Structure 18, 1199-1209.
4. Loh, P. G., Yang, H. S., Walsh, M. A., Wang, Q., Wang, X., Cheng, Z., Liu, D., and Song, H. (2009) Structural basis for translational inhibition by the tumour suppressor Pdcd4, The EMBO journal 28, 274-285.
5. Rossi, F., Garavaglia, S., Montalbano, V., Walsh, M. A., and Rizzi, M. (2008) Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia, Journal of Biological Chemistry 283, 3559-3566.
6. Ling, S. H. M., Decker, C. J., Walsh, M. A., She, M., Parker, R., and Song, H. (2008) Crystal structure of human Edc3 and its functional implications, Molecular and cellular biology 28, 5965-5976.
7. Gut, H., King, S. J., and Walsh, M. A. (2008) Structural and functional studies of Streptococcus pneumoniae neuraminidase B: An intramolecular trans-sialidase, FEBS letters 582, 3348-3352.
8. Cipriani, F., Felisaz, F., Launer, L., Aksoy, J. S., Caserotto, H., Cusack, S., Dallery, M., Di-Chiaro, F., Guijarro, M., and Huet, J. (2006) Automation of sample mounting for macromolecular crystallography, Acta Crystallographica Section D: Biological Crystallography 62, 1251-1259.
9. Beteva, A., Cipriani, F., Cusack, S., Delageniere, S., Gabadinho, J., Gordon, E., Guijarro, M., Hall, D., Larsen, S., and Launer, L. (2006) High-throughput sample handling and data collection at synchrotrons: embedding the ESRF into the high-throughput gene-to-structure pipeline, Acta Crystallographica Section D: Biological Crystallography 62, 1162-1169.
10. Chen, N., Walsh, M. A., Liu, Y., Parker, R., and Song, H. (2005) Crystal Structures of Human DcpS in Ligand-free and m7 GDP-bound forms Suggest a Dynamic Mechanism for Scavenger mRNA Decapping, Journal of molecular biology 347, 707-718.
11. van den Heuvel, R. H. H., Westphal, A. H., Heck, A. J. R., Walsh, M. A., Rovida, S., van Berkel, W. J. H., and Mattevi, A. (2004) Structural studies on flavin reductase PheA2 reveal binding of NAD in an unusual folded conformation and support novel mechanism of action, Journal of Biological Chemistry 279, 12860-12867.
12. Surdo, P. L., Walsh, M. A., and Sollazzo, M. (2004) A novel ADP-and zinc-binding fold from function-directed in vitro evolution, Nature structural & molecular biology 11, 382-383.
13. Kong, C., Ito, K., Walsh, M. A., Wada, M., Liu, Y., Kumar, S., Barford, D., Nakamura, Y., and Song, H. (2004) Crystal Structure and Functional Analysis of the Eukaryotic Class II Release Factor eRF3 from S. pombe. Molecular cell 14, 233-245.
14. Osipiuk, J., Walsh, M. A., and Joachimiak, A. (2003) Crystal structure of MboIIA methyltransferase, Nucleic acids research 31, 5440-5448.