Studies in multi-resistance mechanisms: small multidrug resistance proteins

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My group asks the question; what biochemistry and physiology allows bacteria to deal with a variety of antimicrobial agents within a class, rather than a specific compound? Within this theme we have studied resistance/tolerance to a wide variety of metals including the so-called heavy metals. Through these questions we explore proteins found in the cell membrane that mediate the resistance. This area of research has led to the exploration of the fundamental understanding of microbial physiology, biomembranes, and the structure and function of membrane proteins. This proposal will concentrate primarily on the small multidrug resistance (SMR) family of proteins, which transport quaternary cation compounds and DNA interchelating dyes used as antiseptics. A fascinating aspect of multi-drug resistance systems is that there is both specificity and promiscuity in substrate ligand recognition. The SMR proteins transport a seemingly wide diversity of compounds with little chemical commonality, yet they still display amazing selectivity. Key research areas that will be investigated in this grant term include: i) Investigations into the structural properties of the SMR protein members; ii) The biochemical nature of ligand binding to these transporters; iii) Exploring natural substrates and functions of SMR proteins. Our group will utilize a number of biochemical, molecular biology, and biophysical approaches to study these directions. Our hypothesis lies in the plastic nature of the SMR protein structure and its multimeric states and that different ligands stabilize multimers differently. The long-term goal of these studies is to provide a biochemical and biophysical picture of folding, stability, ligand specificity, function and the biochemical mechanism of SMR proteins. Thus providing an overall understanding of membrane proteins and multi-resistance mechanisms.