Dr Matthew Doyle
School of Medical Sciences
Group Leader: Bacterial Outer Membrane Biogenesis Laboratory
Research Program Lead: Sydney Anti-bacterial Accelerator (SABA)
Member: Sydney Infectious Diseases Institute
Member: Centre for Drug Discovery Innovation
2022-current: Senior Lecturer, School of Medical Sciences, The University of Sydney
I am captivated by the ability of membrane proteins to reach the correct location within the cell and fold properly – these are essential properties for life!
One of my lab’s core goals is to explain how newly synthesised outer membrane proteins (OMPs) are directed to, folded into, or transported across the Gram-negative bacterial outer membrane. Future innovation of antibiotics, understanding how OMPs enable bacterial infections, and the optimal design of industrial bioprocess technologies, are all dependent on fully understanding these protein transport pathways. To investigate OMP biogenesis we combine methods from a range of disciplines such as bacteriology, biochemistry, structural biology, and drug discovery.
Fundamental Science:
What are the steps of OMP transport and folding?
The steps of OMP folding into the outer membrane remain unsolved but we know that they are catalysed by protein machines that contain a conserved Omp85-superfamily core protein subunit. One type of Omp85 protein, BamA, is essential for cell viability, is ubiquitous in all Gram-negative bacteria, and essential homologs of BamA are found in eukaryotic organelles of bacterial origin (e.g. mitochondria and chloroplast). We are currently investigating the notion that Omp85 proteins can deploy a core molecular mechanism to fold diverse types of OMPs.
What drives OMP folding?
The energy source(s) that drive OMP folding have remained an amazing mystery. At the outer membrane OMP folding occurs without the aid of gradient driven pumps or other energy sources such as ATP. We are currently investigating the exciting idea that Omp85-machines harness the tensile properties of the outer membrane itself to aid OMP folding at the molecular level.
Translational Science:
Aside from their fundamental importance for life, Omp85-machine function has recently become a topic of intense international interest since the discovery of peptide-like compounds in 2019 that kill bacteria by targeting BamA. Compounds that inhibit BamA function at the bacterial cell surface promise to be a strong counter to the mounting crisis of drug-resistant bacterial infections that now claim >1.27 million lives annually. We are currently investigating the mechanism of action of these new drug-leads as well as designing approaches to discover novel antibiotics.
2020: National Institute of Diabetes and Digestive and Kidney Diseases Director’s Award (Scientific) – Individual
2020: Boomerang Award (ASBMB)
2018: NIH Research Mentor Award
2015: The Doctoral Research Medal – The University of Adelaide
| Project title | Research student |
|---|---|
| Mechanism And Inhibition Of Phospholipid Transport In Gram-Negative Bacteria | Alanah EISENHUTH |
| Development of the First Two-Partner Secretion System Inhibitors | Alfred HARTOJO |
Publications
Selected Grants
2023
- Uncovering the two-partner secretion mechanism and novel antimicrobials, Cotter P, Doyle M, National Institutes of Health (USA)/Research Grant
- Bacterial Omp85 surface proteins as novel targets for the discovery of antibiotic and anti-virulence drugs, Doyle M, Centre for Drug Discovery Innovation/Sydney ID Seed Funding
2022
- Bacterial Omp85 surface proteins as novel targets for the discovery of antibiotic and anti-virulence drugs, Doyle M, Centre for Drug Discovery Innovation/Sydney ID Seed Funding
- Bacterial Outer Membrane Biogenesis Lab Start-up (NEW ACADEMIC STAFF FUNDING SCHEME), Doyle M, Faculty of Medicine and Health/Startup funds support
- Discovery of novel antibiotics by targeting essential Gram-negative surface structures, Doyle M, Sydney Institute for Infectious Diseases (Sydney ID)/Strategic Funding
Preprint Publications
- Hanson S, Doyle M, Bernstein H.The patatin-like protein PlpD forms novel structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane. BioRxiv; 2023. [More Information]