Studies in multi-resistance mechanisms: small multidrug resistance proteins

我的小组问这个问题；什么样的生物化学和生理学允许细菌处理一类内的各种抗菌剂，而不是特定的化合物？在这个主题中，我们研究了对各种金属的抗性/耐受性，包括所谓的重金属。通过这些问题，我们探索在细胞膜中发现的介导耐药性的蛋白质。这一领域的研究导致了对微生物生理学、生物膜以及膜蛋白结构和功能的基本理解的探索。这一建议将主要集中在小的多药耐药（SMR）蛋白家族，它们运输季阳离子化合物和用作防腐剂的DNA互螯合染料。多药耐药系统的一个令人着迷的方面是在底物配体识别中既有特异性又有混杂性。SMR蛋白运输的化合物似乎种类繁多，几乎没有化学共性，但它们仍然表现出惊人的选择性。本资助期将研究的重点研究领域包括：i)研究SMR蛋白成员的结构特性；ii)与这些转运体结合的配体的生化性质；iii)探索SMR蛋白的天然底物和功能。我们的小组将利用一些生化、分子生物学和生物物理学的方法来研究这些方向。我们的假设在于SMR蛋白结构及其多聚体状态的可塑性，以及不同配体稳定多聚体的方式不同。这些研究的长期目标是提供SMR蛋白的折叠、稳定性、配体特异性、功能和生化机制的生化和生物物理图谱。从而提供了对膜蛋白和多重耐药机制的全面了解。

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.