Insight into antibiotic resistance of pathogenic bacteria via structural studies of a multidrug transporter

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Antibiotic resistance is a major global health concern. One of the mechanisms that infectious bacteria have evolved to resist the effects of antibiotics is that of multidrug efflux. This process is mediated by molecular pumps, made of protein, that are embedded in the fatty membranes that surround the bacterial cell. An understanding of the structure and mechanism of these membrane proteins is vital if we are to understand how they recognise and transport their antibiotic substrates and, in turn, use that knowledge to our advantage in the fight against bacterial infections. Although membrane proteins are important biological molecules that represent about one third of all the proteins made by a typical cell, and nearly half of them are targets of drugs on the market today, the structures of relatively few membrane proteins have been solved. One of the reasons for this is the challenge of working with proteins that are embedded in the oil-like environment of biological membranes. This means they first need to be isolated from their membrane environment using detergents before they can be highly purified to free them of contaminants. The purified protein-detergent complex then needs to be crystallised and exposed to X-rays in order to obtain a detailed, three-dimensional atomic structure. We have isolated, purified and grown crystals of a membrane protein from E. coli that plays a role in the transport of a broad range of antibiotics out of the cell, thereby contributing to multidrug resistance. This is a vital first step towards solving the structure of this transporter protein using a technique called X-ray crystallography. The structural information gained will provide insight into how these proteins recognise and bind to a diverse range of antibiotic substrate molecules and how they use energy to drive those substrates out of the cell. This information, in combination with biochemical studies designed to test if the protein performs other physiologically relevant functions, could be of use in the fight against antibiotic resistance in harmful bacteria.