Professor Sir Michael Ferguson

Insect-transmitted protozoan parasites cause widespread and debilitating diseases in man and domestic livestock throughout the tropics. Examples of diseases caused by trypanosomatid parasites include African sleeping sickness (caused by Trypanosoma brucei and transmitted by tsetse flies), Chagas disease (caused by Trypanosoma cruzi) and kala-azar, espundia and oriental sore (caused by the Leishmania). There are no vaccines against these diseases and most of the available drug treatments are toxic and/or ineffective.

Parasite surface molecules must protect the organisms and enable them to identify, and interact with, cells of both the insect vector and the animal host. Many trypanosomatid parasite surface molecules are either glycosylphosphatidylinositol (GPI) anchored glycoproteins or GPI-related glycolipids (Figure.1 below).

The parasite GPI biosynthetic pathway, and the pathways that assemble the sugar nucleotides that fuel it and the protein O- and N-glycosylation pathways, are validated targets for the development of new chemotherapeutic agents.

See Figure 2 below - The structural, biosynthetic and metabolic repertoires of Trypanosoma brucei

Our research is multi-disciplinary and involves defining:

• The "structural repertoire" of the parasite glycoproteins (Figures.1 & 3 see below)
• The "biosynthetic repertoire" of necessary glycosyltransferases and processing enzymes needed to create the structural repertoire (Figure 2 below)
• The "metabolic repertoire" of sugar nucleotides, and their biosynthetic and transporter proteins, needed to fuel the biosynthetic repertoire (Figures.2 & 4 below)

See Figure 3 below - The structural repertoire of known glycosidic linkages in Trypanosoma brucei

These goals involve:

(A) The isolation and analysis of parasite surface molecules and sugar nucleotide metabolites using advanced mass spectrometric methods (1-3).

(B) Bioinformatics, gene-knockout, cell biology and advanced mass spectrometric methods, to identify, localise and study the functions of glycoprotein (GPI anchoring and protein N-glycosylation) glycosyltransferases and sugar nucleotide biosynthetic enzymes (4-13).

See Figure 4 below - The metabolic repertoire of sugar nucleotide assembly in Trypanosoma brucei, T.cruzi and Leishmania major. Adapted from Turnock and Ferguson (2007) Eukaryotic Cell 6, 1450-1463

(C) The use of quantitative (eg. SILAC) proteomics (14,15) and phosphoproteomics (16,17) methods to determine organellomes, signalling pathways and to identify the modes of action of drugs developed from phenotypic screens. 

(D) Enzymology to define the properties and substrate specificities of enzymes involved in protein glycosylation, GPI anchor biosynthesis and sugar nucleotide assembly (7-10, 18-21).

(E) Drug Discovery, including X-ray crystallography and molecular modelling of drug target enzymes (7-10, 21,22) (Fig.5) (in collaboration with Bill Hunter, Daan van Aalten and the Structural Genomics Consortium), computational chemistry, high-throughput screening and molecular pharmacology (in collaboration with David Gray) and medicinal chemistry (in collaboration with Ian Gilbert and Paul Wyatt).

We also have ongoing studies on the proteome and phosphoproteome of T.brucei (14-17).

See Figure 5 below - Crystal structure and active site of T.brucei UDP-glucose 4'-epimerase, a drug target for African sleeping sickness

Our ultimate aim is to discover new anti-parasite therapeutic agents for clinical trials through our unique Drug Discovery Unit (23).

Biomarker Discovery and Diagnostics Development

In addition to our work on parasite glycobiology, we use our expertise in mass spectrometry and proteomics to develop lateral flow diagnostic devices for human and animal trypanosomiasis (24-27).