Associate Professor Christopher McDevitt
|Org Unit||Molecular and Cellular Biology|
|Telephone||+61 8 8313 0413|
|Location||Floor/Room 4 13 , Molecular Life Sciences Building , North Terrace|
2016 - Present – Associate Professor, School of Biological Science
2016 - Present – Deputy Director, Australian Centre for Antimicrobial Resistance Ecology
2014 - Present – Deputy Director, Research Centre for Infectious Disease
2012 - Present – Group Leader - Chemical Biology of Bacterial Pathogens Laboratory
2008 - 2011 – Independent Research Fellow (Discipline of Microbiology and Immunlogy, University of Adelaide)
2005 - 2008 – Senior Postdoctoral Research Associate (Nuffield Department of Clinical Laboratory Sciences, Oxford)
2002 - 2005 – Postdoctoral Research Associate (Department of Biochemistry, Oxford)
1998 - 2002 – Ph.D (University of Queensland, Australia)
2002 – Ph.D, University of Queensland, Australia.
1997 – Bachelor of Science (Honours, Class I), University of Queensland, Australia.
2011 - Research Career Development Network Mid-Career Researcher Award (University of Adelaide)
2007 - EPA Cephalosporin Junior Research Fellow (Linacre College, University of Oxford)
For the most up to date information see my website mcdevittlab.org
What are we interested in?
The primary research interest of my group is the role of membrane proteins in bacterial pathogenesis.
Membrane proteins account for about one-third of the proteins encoded by the genome but the challenges in their isolation and handling have meant that they have remained relatively poorly characterised compared to their soluble counterparts.
The focus of research in my group will be to characterise the role of specific membrane proteins and their involvement pathogenicity by mediating bacterial virulence, by use of molecular, biochemical and biophysical techniques.
See the Chemical Biology of Bacterial Pathogens laboratory website for more information.
What are we working on?
Metal Ion ABC Transporters of Pathogenic Bacteria
Bacterial infections are highly dependent on metal ion micronutrients . The high affinity uptake pathways are encoded for by ABC permeases that acquire metal ions from the extracellular environment. Of particular interest to our group are the metal ions manganese and zinc. Manganese has important roles during infection and colonization, where it serves in carbon metabolism and oxidative stress response whereas zinc is an essential cofactor for numerous cellular functions. The manganese and zinc ABC uptake transporters have been shown to be essential for the virulence of a number of human pathogens.
1. Manganese uptake in Streptococcus pneumoniae and other pathogens
Bacterial pathogens must scavenge their metal ions from the host environment in order to mediate virulence. Streptococcus pneumoniae is the world's foremost bacterial pathogen and is responsible for more than one million deaths every year. In terms of relative disease burden, it is the largest bacterial killer of young children and kills more children every year than AIDs, tuberculosis and malaria combined. However, its ability to infect and cause disease are dependent on the acquistion of metal ions, one of which is the transition row metal ion manganese. Loss of manganese uptake completely prevents its ability to cause disease.
Our group seeks to understand how S. pneumoniae, and other pathogens, scavenge manganese from the host environment. Although it was known an ABC importer was involved in this process, the underlying details were pooly understood. Recently we revealed the mechanism by which S. pneumoniae scavenges manganese from the host environment and how another metal ion, zinc, interfered with this process. We found that the manganese recruiting protein, PsaA, used a 'spring-hammer' mechanism to bind metal ions, in which half of the protein pivoted and closed over the other half .
There are still many unanswered questions that we are currently investigating. These include how is this ABC importer is selective for manganese ions, how are these ions are translocated into the bacterial cell, and how does the host prevent manganese from being scavenged by the bacteria during infection. Answering these questions will provide the necessary information to design the next generation of antimicrobial agents to target this essential bacterial pathway.
2. Zinc homeostasis in Streptococcus pneumoniae
Zinc is the second most abundant transition row element in biological systems. This metal ion has crucial roles in numerous cellular processes such as transcription, translation, catalysis and metabolism. As with all nutrients, pathogenic bacteria must scavenge zinc from the host in order to mediate disease.
Our studies have shown that manganese and zinc have an unusual relationship in S. pneumoniae, where zinc can actually block the manganese ABC importer. So we are seeking to understand how zinc is acquired and managed in this organism. Recently work from our lab identified that zinc uptake in S. pneumoniae, although similar to manganese uptake, was regulated in a more complex manner. Intriguingly zinc was recruited by 2 proteins, AdcA and AdcAII. A number of possible models have been proposed for how these proteins work together to recruit zinc.
Work in our group is focused on understanding how zinc is sensed by S. pneumoniae, how is zinc managed once it has been translocated into the cell, and how does the host utilise zinc during infection. The answers we obtain to these questions will lead to new ways to target this major human pathogen and its need for zinc.
3. Characterisation of Pseudomonas aeruginosa ABC transporters
ABC transporters are also associated with multidrug resistance in a broad range of different organisms. There are 4 uncharacterised ABC efflux pumps in P. aeruginosa 3 of which have roles in multidrug resistance. This project will focus on identifying the precise roles and biochemical functions of these proteins and determine whether they contribute to virulence of P. aeruginosa in vivo.
A. Colourised scanning electron micrograph of Pseudomonas aeruginosa (Copyright: CDC/Janice Haney Carr) B. Topology, structure, and conformations of distinct states of type II ABC importers. Philos Trans R Soc Lond B Biol Sci. (2009) 364:239–245
For more information see the Chemical Biology of Bacterial Pathogens laboratory website.
What techniques do we use?
These studies utilises a range of different molecular, biochemical and biophysical techniques including:
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Key publications relevant to current research
Refereed Journal Articles
- Plumptre, C.D., Hughes, C.E., Harvey, R.M., Eijkelkamp, B.A.,
McDevitt, C.A. and Paton, J.C. (2014) Overlapping functionality of the
Pht proteins in zinc homeostasis of Streptococcus pneumoniae. Infection and Immunity. doi:10.1128/IAI.02155-14 [pdf]
- van Wonderen J.H., McMahon R.M., O'Mara M.L., McDevitt C.A., Thomson A.J., Kerr I.D., MacMillan F., and Callaghan R. (2014) The central cavity of ABCB1 undergoes alternating access during ATP hydrolysis. FEBS Journal. 281:2190-201 [pdf]
- Eijkelkamp, B.A., Morey, J.R., Ween, M.P., Ong, C.Y., McEwan, A.G., Paton, J.C., and McDevitt, C.A. (2014) Extracellular zinc competitively inhibits manganese uptake and compromises oxidative stress management in Streptococcus pneumoniae. PLoS ONE. 9:e89427 [pdf]
- Plumptre, C.D.*, Eijkelkamp, B.A.*, Morey, J.R., Behr, F., Couñago, R.M., Ogunniyi, A.D., Kobe B., O'Mara, M.L., Paton, J.C., and McDevitt, C.A. (2014) AdcA and AdcAII employ distinct zinc acquisition mechanisms and contribute additively to zinc homeostasis in Streptococcus pneumoniae. Molecular Microbiology. DOI: 10.1111/mmi.12504 [pdf] [*equal first author]
- Couñago, R.M.*, Ween, M.P.*, Begg S.L., Bajaj, M., Zuegg, J., O'Mara, M.L., Cooper, M.A., McEwan, A.G., Paton, J.C., Kobe, B., and McDevitt, C.A. (2014) Imperfect coordination chemistry facilitates metal ion release in the Psa permease. Nature Chemical Biology. 10:35-41. [pdf] [*equal first author]
- Pollock, N.L., McDevitt, C.A., Collins, R.F., Niesten, P.H.M., Prince, S., Kerr, I.D., Ford, R.C., and Callaghan, R. (2014) Improving the stability and function of purified ABCB1 and ABCA4: The influence of membrane lipids. Biochim Biophys Acta. 1838:134-47. [pdf]
- Heng S., McDevitt C.A., Stubing D.B., Whittall J.J., Thompson J.G., Engler T.K., Abell A.D. and Monro T.M. (2013) Microstructured optical fibers and live cells: a water-soluble, photochromic zinc sensor. Biomacromolecules. 14:3376-9. [pdf]
- McDevitt, C.A., Ogunniyi, A.D., Valkov, E., Lawrence, M.C., Kobe, B., McEwan, A.G., and Paton, J.C. (2011) A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathogens 7:e1002357 [pdf]
Research highlight in Nature Reviews Microbiology - David, R. (2012)
- Ogunniyi, A.D., Mahdi, L.K., Jennings, M.P., McEwan, A.G., McDevitt C.A., Van der Hoek, M.B., Bagley, C.J., Hoffman, P., Gould, K.A., and Paton, J.C. (2010) Central role of manganese in regulation of stress responses, physiology and metabolism in Streptococcus pneumoniae. Journal of Bacteriology 192:4489-97. [pdf]
- McDevitt, C.A., Collins, R.F., Kerr, I.D., and Callaghan, R. (2009) Purification and structural analyses of ABCG2. Advanced Drug Delivery Reviews 61:57-65 [pdf]
- McDevitt, C.A., Crowley, E.H., Hobbs, G., Starr, K., Kerr, I.D., and Callaghan, R. (2008) Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2? FEBS Journal 275:4354-62 [pdf]
- McDevitt, C.A., Shintre, C.A., Grossmann, G.J., Pollock, N.L., Prince, S.M., Callaghan, R., Ford, R.C. (2008) Structural insights into P-glycoprotein (ABCB1) by small angle X-ray scattering and electron crystallography. FEBS Letters 582:2950-6 [pdf]
- McDevitt, C.A., Sargent, F., Palmer, T., and Berks, B. C. (2006) Subunit composition and in vivo substrate-binding characteristics of Escherichia coli Tat protein complexes expressed at native levels. FEBS Journal 273:5656-68 [pdf]
- McDevitt, C.A., Collins R.F., Conway M., Modok S., Storm J., Kerr I.D., Ford R.C. and Callaghan R., (2006) Purification and 3-D structural analysis of oligomeric human multidrug transporter ABCG2. Structure 14:1623-32 [pdf]
- Gohlke, U., Pullen, L., McDevitt, C.A., Porcelli, I., Palmer, T., Sabil, H.R. and Berks, B.C. (2005) The TatA component of the twin-arginine protein transport system forms channel complexes of variable diameter. Proc. Natl. Acad. Sci. 102:10482-10486 [pdf]
- McDevitt, C.A., Hicks, M.G., Palmer, T., and Berks, B.C. (2005) Biochemical characterisation of null phenotype mutant Tat receptor complexes. Biochemical Biophysical Research Communications 329:693-8
- McEwan, A.G., Bernhardt P.V., Creevey, N., Hanson, G.R., and McDevitt, C.A. (2004) Ion motive electron transfer pathways involving type II molybdoenzymes of the DMSO reductase family. BBA-Bioenergetics 1658:16.
- McDevitt, C. A., Hanson, G. R., Noble, C., Cheesman, M. R., and McEwan, A. G. (2002) Characterisation of the redox centres from Dimethylsulfide Dehydrogenase of Rhodovulum sulfidophilum. Biochemistry 41:15234-44
- McEwan, A.G., Ridge, J.P., McDevitt, C.A., and Hugenholtz, P. (2002) The DMSO reductase family of microbial molybdenum enzymes; molecular properties and role in the dissimilatory reduction of toxic elements. Geomicrobiology Journal 19:3-21
- McDevitt, C.A., Hugenholtz, P., Hanson, G.R., and McEwan, A.G. (2002) Molecular analysis of Dimethylsulfide Dehydrogenase from Rhodovulum sulfidophilum; its place in the DMSO reductase family of microbial molybdopterin-containing enzymes. Molecular Microbiology 44:1575-87
- Hanson, G.R., McDevitt, C.A., and McEwan, A.G. (2001) Dimethylsulfide dehydrogenase from Rhodovulum sulfidophilum: EPR spectroscopy and biochemical analysis reveal its place in the DMSO reductase family of molybdenum enzymes. Journal of Inorganic Biochemistry 86:248.
- McDevitt, C., Burrell, P.C., Blackall, L.L., and McEwan, A. G. (2000) Aerobic nitrate respiration in a nitrite oxidising bioreactor. FEMS Microbiology Letters 184:113-118.
- Couñago R.L., McDevitt C.A., Ween M.P., Kobe B. (2012) Prokaryotic substrate-binding proteins as targets for antimicrobial therapies. Current Drug Targets 3:1400-10 [pdf]
- Lewis, V.G., Ween, M.P., and McDevitt C.A. (2012) The role of ATP-binding cassette transporters in bacterial pathogenicity. Protoplasma. 249:919-942 [pdf]
- Lehane, A.M., McDevitt, C.A., Kirk, K., and Fidock, D.A. (2012) Degrees of chloroquine resistance in Plasmodium - is the redox system involved? Int. J. Paras. Drugs Drug Res. 1:47-57 [pdf]
- Crowley, E. H., McDevitt, C.A., and Callaghan, R. (2009) Generating inhibitors of P-glycoprotein (ABCB1); where to now? In “Multi-Drug Resistance in Cancer” (editor J. Zhou) Methods Mol Bio. 596:405-32 [pdf]
- McDevitt, C.A., and Callaghan R. (2007) How can we best use structural information on P-glycoprotein to design inhibitors? Pharm and Therap. 113:429-41 [pdf]
- McEwan, A.G., Kappler, U. and McDevitt, C.A. (2004) Molybdenum enzymes in bacterial respiration. In “Respiration in Archaea and Bacteria” (editor D. Zannoni) Kluwer Academic Publishers. p.175-202
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