Soares da Costa - Antibiotic and herbicide discovery
Resistance to current antibiotics and herbicides represents a major threat to global health and food security. Despite a continuous rise in resistance worldwide, there has been a lack of antibiotics or herbicides with a new mode of action introduced to the market for the past 30 years.
The overall focus of our laboratory is to define the structure, function and regulation of essential proteins in bacteria and plants to guide the development of new classes of antibiotics and herbicides. Specifically, we aim to target multiple proteins simultaneously in essential biosynthetic pathways. Combining such multivalent inhibitors as an antibiotic or herbicide ‘cocktail’ provides a novel strategy for reducing the downstream development of resistance and has the potential to improve efficacy through synergism.
Research areas
Validation and characterisation of novel antibiotic and herbicide targets
In this project, novel antibiotic and herbicide targets are initially validated by generating gene knockouts in pathogenic bacteria and weeds employing contemporary techniques such as recombineering (in collaboration with Dr Mark Sutton, Public Heath England), dsRNA (in collaboration with Dr Kim Plummer, AgriBio) and CRISPR/Cas9 (in collaboration with Dr Anthony Gendall, AgriBio). Once targets are identified, the structure, function and regulation of these proteins are characterised using a wide range of biochemical and biophysical techniques, including recombinant protein expression & purification, enzymology, mass spectrometry, circular dichroism spectroscopy, analytical ultracentrifugation and structural biology (in collaboration with Dr Santosh Panjikar, Australian Synchrotron).
Design and characterisation of novel antibiotic and herbicide classes
This project focuses on the design and characterisation of small molecules inhibitors of essential enzymes in bacteria and plants. Specifically, new compounds are developed using traditional ligand-based design (in collaboration with Dr Belinda Abbott, Department of Chemistry and Physics), high throughput chemical screening, in situ click chemistry (in collaboration with Prof John Moses and Dr Andrew Barrow, Department of Chemistry and Physics) and innovative docking simulations. The efficacy of these compounds are assessed using (i) dose-response enzyme assays, (ii) microscale thermophoresis and surface plasmon resonance to measure binding affinity, (iii) co-crystallisation studies to determine mode of binding, (iv) bacterial or plant growth assays, (v) mammalian cell toxicity screens, and (vi) resistance studies to define the potential and frequency for resistance to emerge.
