Understanding and Overcoming Multi-Drug Efflux Pumps in Disease

The phenomenon of resistance to chemotherapy continues to plague treatment of cancer and bacterial infection. Whilst drug resistance should be considered a multi-factorial process the original “Multidrug Efflux Systems” GRC in 2003 highlighted the prominence and impact of drug efflux pumps in the phenotype. The long-term mission statement of the scientific community at this GRC was to provide a molecular description of the multidrug efflux process and to design inhibitors to overcome the actions of the pumps responsible for the phenomenon. The second GRC in 2005 focussed on molecular aspects of resistance to chemotherapy including regulation and bio-energetics. In addition, there was considerable discussion of the clinical relevance and the wider biological impact of multidrug efflux pumps. Efforts to understand the mechanism of multidrug efflux has advanced steadily with significant input from active participants of the previous GRCs.

However, a complete understanding requires the input of structural data and unfortunately this remains a difficult task for membrane proteins. Provision of structural data has begun in earnest and advances in expression systems and extraction techniques have brought us to the cusp for many efflux pumps. This aspect of research will be a particular focus for the 2009 “Multidrug Efflux Systems” meeting. Structural information will comprise high resolution X-ray and electron microscopy data in addition to molecular modelling for proteins whose structures are not fully understood. A particular emphasis will be to relate structural information with biochemical data on drug-protein interaction and chemical synthesis of inhibitors. The emerging structural information thus heralds an exciting period in the quest to circumvent multidrug resistance in bacterial infections and cancer.