Diversity-Oriented Synthesis and Chemical Genetics of New Antibacterials

这一奖学金和研究拨款将支持的研究的共同主题是开发新的方法和技术来发现具有生物活性的小分子，如抗生素和其他药物。新的方法有两个特殊的方面，我们将集中在：1.面向多样性的合成，和2.3-D小分子微阵列技术。以多样性为导向的合成是有机合成中的一个新概念，其目的是高效地合成结构多样的小分子。我们将进行面向多样性的合成，以提供迄今为止结构多样性范围最高的产品。由于结构多样性在某种程度上是主观的，我们还将开发软件来分析小分子集合。我们制造的化合物将被测试它们杀死有害细菌的能力。三维小分子微阵列是玻璃显微镜载玻片(25x75毫米)，其顶部表面有数千个独立的聚合物斑点，每个斑点都含有小分子。由于每个单独的斑点都附着着一种不同的化合物，它们可以用来同时测试所有的小分子。这是一种高效的方法，可以在如此小的规模内同时测试如此多的化合物。我们将在这一领域开创新的方法学，以克服现有的问题，如信噪比和表面效应。该奖学金还将使我们完成其他正在研究的合成方法学和潜在的新抗生素的合成，如合成类脂A类似物和群体感应调节剂。

The common theme of the research that this fellowship and research grant will support concerns the development of new approaches and techniques to discover biologically active small molecules, such as antibiotics and other drugs. There are two particular aspects of the new approaches that we will concentrate upon: 1. diversity-oriented synthesis, and 2. 3-D small molecule microarraying technology. Diversity-oriented synthesis is a new concept in organic synthesis, where the aim is to synthesise collections of structurally-diverse small molecules efficiently. We will perform a diversity-oriented synthesis to give products with the highest range of structural diversity to date. As structural diversity is somewhat subjective, we will also develop software to analyse collections of small molecules. The compounds that we make will be tested for their ability to kill bad bacteria. 3-D Small molecule microarrays are glass microscope slides (25 x 75 mm) that have thousands of separate polymer spots on the top surface, which contain small molecules at each spot. As each individual spot has a different compound attached to it, they can be used to test all of the small molecules at the same time. This is a highly efficient way of testing so many compounds at once on such a small scale. We will pioneer new methodology in this area to overcome existing problems such as signal-to-noise and surface effects.The fellowship will also allow the completion of other approaches we are researching in synthetic methodology and synthesis of potential new antibiotics, such as the synthesis of lipid A analogues and quorum sensing modulators.