MRC Innovation Grant.Multi-Targetting of tRNA synthetases: A paradigmshift in combating AMR

对现有抗生素的耐药性在多个层面上威胁着未来的医疗保健，并已被公认为一个全球性问题，其影响与气候变化一样重要。然而，尽管有明确的临床需求，但许多因素导致制药行业中抗菌药物的发现和开发稳步下降。在过去，该领域剩余的制药公司的抗菌研究和开发通常集中在尝试发现抗生素的新靶标或基于现有靶标的活性有限的新化合物。一般来说，这种方法取得的成功非常有限，这意味着我们有越来越少的药物来治疗细菌感染，导致医疗保健危机。很明显，细菌善于选择单基因靶点的耐药药物（即他们的蛋白质产品）并且过去成功的抗微生物化疗靶向存在多种必需活性的活性例如核糖体上的蛋白质合成，负责细胞中DNA超螺旋的蛋白质和实现细菌细胞壁交联的机制。我们已经确定了细菌代谢的另一个领域，它具有这些相似的特性，如果正确定位，可能会为下一代抗菌剂的发现提供一条途径。蛋白质合成本身是如上所述的过去抗微生物发现的黄金领域，其依赖于将单个氨基酸递送至核糖体，所述核糖体通过化学连接活化以转移（t）RNA分子。每种氨基酸都有自己的合成酶，但这些酶中的一些缺乏最初选择正确氨基酸的能力，并且依赖于其他系统来产生正确的氨基酸-tRNA配体产物。正是这种选择过程，我们可以用潜在的药物来规避，从而产生一种新的抗菌化疗路线，这不太可能通过突变来克服耐药性，因为这些潜在的药物需要多个基因的突变。虽然在这个领域有大量现有的生物化学数据可供借鉴，但我们缺乏这一发现过程下一阶段所需的一些三维结构。该项目的目标是提供这些数据。

Antimicrobial resistance to existing antibiotics threats future healthcare at multiple levels and has been acknowledge as a worldwide issue with an impact as important as climate change. However, a number of factors has lead to a steady decline in the discovery and development of antimicrobials in the pharmaceutical industry despite the clear clinical need. The remaining pharmaceutical company antibacterial research and development in this area has focused generally in the past on either attempts to discovery new targets for antibiotics or new compounds with limited activity profiles based on existing targets. Generally this approach has met with very limited success which combined with other factors, means we have a decreasing number of drugs to treat bacterial infection leading to a crisis on healthcare.It is clear that bacteria are adept at the selection of resistance to drugs for single gene targets (i.e. their protein products) and that the successful antimicrobial chemotherapy of the past targets activities where there are multiple essential activities e.g. protein synthesis at the ribosome, the proteins which are responsible for DNA supercoiling in the cell and mechanisms by which cross-linking of the bacterial cell wall is achieved. We have identified another area of bacterial metabolism which has these similar properties and if correctly targeted may provide an avenue for next generation antimicrobial discovery. Protein synthesis, itself a golden area for past antimicrobial discovery as described above, is reliant upon the delivery of single amino acids to the ribosome which are activated by chemical ligation to transfer (t)RNA molecules. Each amino acid has its own synthetase but some of these enzymes lack the ability to select the correct amino acid initially and are reliant on other systems to produce the correct amino acid-tRNA liganded product. It is this selection procedure, which we can circumvent with potential drugs and thus produce a new line of antimicrobial chemotherapy this is less likely to be overcome by resistance through mutation since these potential drugs would require mutations in multiple genes. Whilst there is a great deal of existing biochemical data to draw upon in this field we lack the three-dimensional structures of some which are required for the next stage of this discovery process. The goal of this project will be to produce these data.