Chemical Biology in Drug Discovery Laboratory

Within: Bosch Institute, Discipline of Pharmacology

Head of laboratory

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Overview

Our laboratory uses approaches in chemical biology to discover new drugs and new drug targets.

Our principle interests lie in the discovery of new antibiotics, anticancer agents, metal chelating compounds and protein-based drug targets.

Most recently, we have tuned the properties of a drug used to treat iron overload disease in beta-thalassemia patients, which affects many thousands of newborns per year worldwide. Several compounds show promise for potentially improving the current treatment.

We are using bacteria to produce new drugs by adding to culture medium molecular building blocks that can compete for natural substrates and be incorporated into new compounds.

This approach uses the complex biosynthetic pathways of bacteria, which continue to be unravelled by genome sequencing, to generate molecular diversity.

We work at the interface of chemistry, microbiology and biotechnology, which provides for a dynamic research environment and new ways of approaching problems.

Techniques in our laboratory: synthesis (organic, inorganic, affinity resins), microbiology, protein purification, biomolecule purification (affinity chromatography, HPLC), ESI-MS, NMR spectroscopy.

Research achievements

Iron and bacteria

The Fe(III)-loaded siderophore complex, ferroxamine B.

The Fe(III)-loaded siderophore complex, ferroxamine B.

We study molecules produced by non-pathogenic and pathogenic bacteria called ‘siderophores’, which are low-molecular-weight organic compounds that have a high affinity towards Fe(III).

Under low iron conditions, siderophores are produced by bacteria to sequester iron from the local environment (soil, ocean, human host).

In concert, bacteria upregulate cell surface receptors that avidly recognise the cognate Fe(III)-loaded siderophore complex. Iron is essential for bacterial growth and for establishing an infection. Compounds that prevent regular bacterial iron uptake, therefore, are potential narrow spectrum antibiotic agents.

Our laboratory is studying the antibiotic potential of siderophore-mediated iron uptake from the level of siderophore through to the cognate receptor.

Histone deacetylase inhibitors

Many siderophores contain hydroxamic acid functional groups, which have a high affinity towards Fe(III).

Hydroxamic acid groups also have an affinity towards Zn(II), which is the catalytic biometal at the active site of histone deacetylases, which are a family of enzymes at the forefront of oncology research.

The hydroxamic acid-based inhibitor, Vorinostat, is used for the treatment of cutaneous T-cell lymphoma. In this project, we are designing new inhibitors of histone deacetylases with activity against one or more of the 18 known HDAC isoforms.

Since different HDAC isoforms have been implicated in different types of cancers, there is interest in the potential of isoform-specific HDAC inhibitors as narrow spectrum chemotherapeutic agents.