On the trail of drug resistance. Antibiotics, compounds that are ‘against life’, are typically antibacterial or antifungal drugs, interfering with some structure or process that is essential to growth or survival of these organisms. Related drugs are also used in anticancer treatment. Sadly, several diseases that for many years were sensitive to drug-based therapies are no longer sensitive to the same drugs. We live in an era when drug resistance has spread at an alarming rate. The World Health Organization states that antibiotic resistance is one the three greatest threats to human health. One powerful mechanism of drug resistance is based on the transport of pharmaceuticals from the cell’s interior by multidrug transporters with an extraordinary broad drug specificity. As a result of their activity, the drug concentration in the cell is lowered to subtoxic levels, and, hence, drug toxicity is overcome. There are many interesting questions about these membrane proteins: How do they recognize so many different drugs? Can they be inhibited so that existing drugs can still be used in treatment of diseases? Can drugs be developed that bypass multidrug transporters? In this project we will study the interactions between multidrug transporters and drugs in more detail. The methods used are based on biochemistry, cell biology and biophysics, and include techniques such as DNA cloning, gene expression, molecular modelling, site-directed mutagenesis, and drug binding and transport using radiolabelled and fluorescent substrates. In our research group, we study multidrug transporter from various pathogenic microorganisms and human tumour cells. It is an exciting research field to be part of.
- Van Veen, H.W. (2010) Structural biology: Last of the multidrug transporters. Nature 467: 926-927.
- Gutmann, D.A., Ward, A., Urbatsch, I.L., Chang, G., and Van Veen, H.W. (2010) Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1. Trends Biochem. Sci. 35: 36-42.
- Doshi R, Ali A, Shi W, Freeman EV, Fagg LA, van Veen HW. (2013) Molecular disruption of the power stroke in the ATP-binding cassette transport protein MsbA. J Biol Chem. 288(10):6801-13.