Dr. Christopher Mulligan joined the School of Biosciences in May 2017. Chris obtained a degree in Biochemistry from the University of York (2004). Chris performed his thesis research with Dr. Gavin Thomas at the University of York (2004-2008) and subsequently took up a postdoctoral position in the same lab (2008-2011). Here, Chris studied the structure and function of transporters involved in the uptake of virulence factors into human pathogens. Following his time in York, Chris obtained a visiting fellow position in Dr. Joseph Mindell’s lab in the Membrane Transport Biophysics Section of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) in Maryland, USA. During his time at NIH (2011-2017), Chris studied the structure and mechanism of transport protein families involved in a number of key cellular functions, including neurotransmission and metabolic regulation.
Transport proteins play a major role in crucial cellular processes in all forms of life; from the uptake of nutrients and virulence factors to the extrusion of toxins (including antibiotics) in bacteria, as well as the regulation of neurotransmission and metabolism in mammals.
In humans, improper regulation and mutations in transporters are often associated with disease states like ALS, Alzheimer’s disease and epilepsy. Whereas, in bacteria, transporters contribute substantially to the virulence of human pathogens and their resistance to antibiotics, making them prime targets for new therapeutics. In addition, transporters are also key players in industrial biotechnology. Bacterial cell factories that are used to produce high value chemicals for industrial and medical purposes rely heavily on transport proteins to take up precursors and extrude the final products.
Transport proteins are highly dynamic molecular machines, most of which actively pump their substrates across the membrane fueled by an energy source; usually either ATP hydrolysis or electrochemical gradients (H+ and Na+ gradients). My lab uses a combination of biochemical, biophysical and microbiological techniques to understand the molecular mechanisms of transport proteins; how they recognise compounds, how they harness an energy source to pump compounds across the membrane, and how they move during transport. The more we understand about the mechanism of transporters, the better placed we will be to manipulate their function; either inhibiting them if they have undesirable effects, for example, antimicrobial resistance; or harnessing and enhancing their capabilities if they are useful, for example, for applications in industrial biotechnology.
MSc-R projects available for 21
Probing the mechanism of INDY (I’m not dead yet) transporters: a target for the treatment of cancer, diabetes and obesity.
In eukaryotic cells, disrupting the activity of INDY transporters can extend lifespan, reduce cancer cell proliferation, and protect against metabolic disease such as diabetes and obesity. To develop inhibitors for INDY proteins, we first need to understand their transport mechanism.
In this project, we will investigate the mechanism of the bacterial representative of this family, VcINDY. We will probe substrate and inhibitor interactions, and proteins dynamics using biochemical and biophysical approaches. The student will receive training in molecular biology techniques, such as site-directed mutagenesis, integral membrane protein expression and purification, transporter characterisation, protein biochemistry and biophysical techniques.
Enhancing a microbial solution to drastic plastic pollution.
Phthalic acids (PA) are major constituents of plastics, acting as either part of the polymeric structure (e.g. in polyethylene terephthalate, PET) or as essential non-covalently associated plasticisers. PA plasticisers, which have carcinogenic properties, readily leach out of waste plastics leading to contamination of the environment, and are classified as major man-made priority pollutants due to their ability to cause ill health in both humans and animals.
In this project, we will interrogate the structure and mechanism of predicted bacterial PA transport proteins that are currently very poorly understood. To do this, we will use an integrated approach combining molecular biology, biochemical and biophysical analyses, microbiological approaches. The goal of this project is to further our understanding of the PA uptake mechanisms that bacteria employ to remove this major pollutant from the environment. Ultimately, we will use this knowledge to improve efficiency of the PA breakdown, which has great industrial potential.
The path to least resistance: probing the mechanism of integral membrane transport proteins essential for antimicrobial resistance in bacteria.
Antimicrobial resistance is a major global health concern. One of the most effective mechanisms bacteria have developed to resist the effects of antimicrobial agents is to use drug efflux transporters to pump them out of the cell before they can do any damage. Understanding the structure and function of these proteins will lay the foundation for the development of future inhibitors, which could be used to enhance the efficacy of current antimicrobials and breathe new life into antimicrobials rendered ineffective due to the development of resistance.
In this project, we will elucidate the functional mechanism of a family of integral membrane transport proteins that strongly influence the antibiotic resistance of several bacterial pathogens. This project will take an integrated approach to probing the structure and function of these membrane proteins, which will include protein biochemistry, biophysical approaches and microbial phenotypic assays.