Research Network for Metals in Medicine

 

 

Professor Alastair McEwan

BSc(Leeds), PhD(Birmingham)

Position: Professor, Department of Microbiology & Parasitology

Affiliation: The University of Queensland School of Molecular and Microbial Sciences

Postal Address:
School of Molecular & Microbial Sciences
The University of Queensland
Brisbane Qld 4072
AUSTRALIA

Phone: +61 (07) 3365 4878
Fax: +61 (07) 3365 4620
Email: mcewan@mailbox.uq.edu.au
Webpage: http://www.biosci.uq.edu.au/micro/academic/mcewan/mcewan.htm


Research Profile

The common research theme in my laboratory is the role of metal ions and oxidation-reduction processes in respiratory processes, biocatalysis, regulation of gene expression, bacterial pathogenicity and biotechnology. The microorganisms that we study include purple phototrophic bacteria, thermophilic archaea and bacterial pathogens.

Specific research themes

Microbial respiratory enzymes: the biogeochemical cycling of elements is largely underpinned by oxidation-reduction processes associated with their use as electron donors and acceptors in photosynthesis or respiration. Microbes are central to these processes and they exhibit extraordinary bioenergetic diversity. Our focus is the dimethylsulfoxide (DMSO) reductase family of molybdenum-containing enzymes which act as terminal reductases in the use of respiratory electron acceptors such as nitrate, S-oxides, N-oxides, (per)chlorate, selenate and arsenate, and as primary dehydrogenases in the use of arsenite, dimethylsulfide, nitrite and formate as electron donors. Enzymes of the DMSO reductase family have conserved structural features and all contain a common molybdenum cofactor. This raises the question of how each enzyme is tuned thermodynamically and in terms of substrate specificity to use a particular electron acceptor or donor. To address this we are focusing on two enzymes of the DMSO reductase family; DMSO reductase and DMS dehydrogenase. This research involves a combination of site-directed mutagenesis and enzymology in conjunction with spectroscopic, electrochemical and structural studies. DMS is the most significant compound in the sulfur cycle in the oceans and it acts as a negative greenhouse gas in the atmosphere. Thus, the enzymes of DMS/DMSO metabolism are of major biogeochemical significance. An interesting additional feature of DMSO reductase and DMS dehydrogenases is their ability to produce chiral sulfoxides, organic synthons of increasing importance

We are also investigating the physiology, biochemistry and molecular ecology of thermophilic archaea involved in the bioleaching of mineral sulfides. These microorganisms grow optimally at around pH2 and a temperature > 70C and respire aerobically with ferrous iron oxidation and sulfur compounds as electron donors. The leaching of iron sulfides by microorganisms is of major importance in the recovery of base metals such as copper, zinc and nickel and we collaborate with BHP Billiton in this research.

Metals and Bacterial Pathogenicity: the acquisition of metal cations from the host is a critical aspect of bacterial pathogenicity. Using a combination of molecular genetics and genomics, biochemistry and cell biology we are investigating mechanisms of iron acquisition and novel mechanisms of resistance to oxidative killing involving manganese, copper-containing proteins and peroxidases. A major aim of this work is to identify potential vaccine candidates or targets for novel antibiotics. Pathogens that are currently under investigation include Neisseria gonorrhoaea, Neisseria meningiditis, Pseudomonas aeruginosa, enteric bacteria and Streptococcus pneumoniae.

The focus of our research on Neisseria gonorrhoaea is to determine how this bacterium survives oxidative stress within the urogenital tract. We have shown that this bacterium possesses a superoxide dismutase-independent oxidative defense system that involves chemical quenching of reactive oxygen species (ROS) using manganous ions. This defense system is critically dependent upon an ABC cassette transporter for Mn(II) known as MntABC. Our current research involves understanding the regulation of gene expression in Neisseria by Mn(II) and determining the chemical basis for Mn(II) quenching of ROS. We have also identified a novel oxidative defense system in Neisseria species that involves Sco, a copper-containing protein that is considered to act as a copper-chaperone in the biogenesis of the CuA centre in mitochondrial cytochrome oxidase. We have also identified a ferrous iron uptake pathway in Pseudomonas aeruginosa that involves a multi-copper oxidase, related to laccases and ceruloplasmin. This pathways may be of widespread importance in bacterial iron assimilation but has been overlooked as a consequence of the focus on siderophore-dependent pathways of Fe(III) uptake.

Selected Publications

  1. McDevitt, CA, Hugenholtz, P, Hanson, GR and McEwan, AG (2001) Molecular analysis of Dimethylsulfide dehydrogenase from Rhodovulum sulfidophilum; its place in the DMSO reductase family of microbial molybdopterin-containing enzymes. Mol. Microbiol. 44 1575-1587.
  2. Ridge, JP, Aguey-Zinsou, K-F, Bernhardt, PV, Brereton, I, Hanson, GR & McEwan AG (2001) Site-directed mutagenesis of dimethylsulfoxide reductase from Rhodobacter capsulatus; characterization of a Y114 - F mutant. Biochemistry 41 15762-15769.
  3. Tseng, H, Srikantha, Y, McEwan AG, Jennings MP (2001) A role for manganese and the MntABC primary transporter in the superoxide dismutase-independent protection of Neisseria gonorrhoeae against oxidative challenge.Mol. Microbiol. 40 1175-1186.
  4. Huston, WM, Jennings, MP and McEwan AG (2001) The Multicopper Oxidase of Pseudomonas aeruginosa is a ferroxidase with a central role in iron acquisition. Mol. Microbiol. 45 1741-1750.
  5. Seib, K.L., Jennings, M.P. & McEwan A.G. (2003) A Sco homologue plays a role in defense against oxidative stress in pathogenic Neisseria. FEBS Lett. 546 411-415.

Facilities

Bacterial molecular genetics, protein expression and characterization.

International Linkages

Russ Hille (Ohio State University, USA)
Susan Bailey (Daresbury Laboratory UK)
Graham George (University of Saskatchewan, Canada)
Michael Appicella (University of Iowa, USA)
Geoff Moore (Centre for Metalloprotein Spectroscopy and Biology, University of East Anglia)