Bacterial multi-resistance mechanisms: Functional studies on a multi-ligand transporter

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My research program is rooted in understanding toxin resistance mechanisms in bacteria. My group asks the question: "what biochemistry and physiology allows bacteria to deal with a variety of biocide agents rather than a specific compound?" We have been studying the resistance to metal ions, various organic pollutants, and industrial biocides. In keeping with past research, we will continue to study the so-called `multi-drug' resistance transporters, focusing on compounds that would be generally classified as antiseptics. Antiseptics are used in a variety of areas including: cosmetics, cleaning agents, hand sanitizers, water treatment and corrosion control in oil and gas pipelines. The group of multi-ligand transporters that we will continue to concentrate on is the bacterial small multidrug resistance (SMR) family of proteins that pumps quaternary cation compounds (QCC) out of the cell. An attraction of studying multi-ligand resistance systems is that there is promiscuity in substrate ligand recognition, yet still specific in ligand selection. The SMR proteins transport a seemingly wide diversity of compounds with little chemical commonality, yet they still display amazing selectivity; how is this done? The primary SMR protein we study is EmrE (Escherichia coli multi-resistance protein E). This grant aims to continue our research on the SMR family of proteins. In this grant cycle, the specific objectives are: i) Define the ligand-binding site(s) of EmrE. ii) Identify other proteins involved in the complete transport system of moving the toxin completely out of the cell. iii) Begin to define some of the biochemistry for the transport of natural substrates of EmrE. iv) Study the influence of ligand on multimeric state and folding of SMR proteins. v) Evaluate the physiological response of bacteria to QCC compounds.***The long-term goal of these studies is to provide a biochemical and biophysical picture of folding, oligomerization, stability, ligand specificity, function, biochemical mechanisms and physiology of SMR proteins, thus contributing to understanding multi-resistance mechanisms and functionality of integral membrane proteins.  Understanding multi-compound resistance in bacteria is key to the development of improving the efficacy of antiseptic compounds and new antimicrobial agents.  The need is reflected in the use of QCCs.  The global market for industrial and institutional cleaning products will exceed $50 billion by 2018, and biocides and disinfectants also represent more than 10% of the market of water treatment agents used worldwide.**