Molecular mechanisms of multidrug binding by the bacterial ABC transporter Sav1866

多药转运体是存在于人体细胞和微生物表面的非常小的分子机器。这些精巧的机器为细胞提供了一种防御机制，以抵御有害的有毒化合物。多药转运体的活性干扰了人类肿瘤和传染性病原微生物的基于药物的控制，也称为“化疗”，其中药物被设计为杀死细胞。多药转运体在细胞内部结合结构不相关的药物和毒素，然后将这些化合物转移到细胞外部，远离药物应该与之相互作用的目标。因此，多药转运体充当药物泵，能够降低细胞内的药物浓度，使这些药物失去活性和无用。由于药物现在已经失去了治疗效果，细胞已经变得“耐多药”。本项目重点研究细菌多药转运体Sav1866，它与人类主要的多药泵之一非常相似。Sav1866是由致病性金黄色葡萄球菌制成的，但我们使用非致病性的食品级细菌乳酸乳球菌来研究该泵的性能。Sav1866特别有趣，因为研究人员最近已经能够确定它的三维结构。在这个项目中，我们研究Sav1866如何识别和结合药物。这一知识可能使我们能够合理地设计新的药物，可以毒害或绕过微生物和人类细胞中这些转运蛋白的活性，以改善癌症和传染病的化疗。

Multidrug transporters are very small molecular machines that are present at the surface of human cells and microorganisms. These ingenious machines provide the cell with a defense mechanism against toxic compounds which are harmful to them. The activity of multidrug transporters interferes with the drug-based control, also termed 'chemotherapy', of human tumours and infectious pathogenic microorganisms, in which drugs are designed to kill the cell. Multidrug transporters bind structurally unrelated drugs and toxins at the inside of the cell, and then move these compounds to the outside of the cell, away from the targets with which the drugs are supposed to interact. Hence, multidrug transporters act as drug pumps that are able to lower the drug concentration inside the cell to levels at which these drugs are inactive and useless. As drugs now have lost their therapeutic effects, the cell has become 'multidrug resistant'. This project focuses on the bacterial multidrug transporter Sav1866, which is very similar to one of the major multidrug pumps in human. Sav1866 is made by the pathogenic bacterium Staphylococcus aureus, but we use the non-pathogenic, food-grade bacterium Lactococcus lactis to study the properties of the pump. Sav1866 is particularly interesting as researchers have very recently been able to determine its three-dimensional structure. In this project, we study how Sav1866 recognizes and binds drugs. This knowledge might allow us to rationally design new drugs that can poison or circumvent the activity of these transport proteins in microorganisms and human cells to improve chemotherapy of cancers and infectious diseases.