1. Identification of bacterial genes involved in antibiotic resistance using whole genome screens

致病细菌的抗生素耐药性已经蔓延，导致一些细菌感染无法治疗，这可能导致患者死亡。细菌可以通过不同的机制对抗生素产生耐药性，其中只有一些机制得到了表征。更好地了解细菌如何抵抗抗生素的作用将有助于制造新的抗生素，可能提供控制耐药性的新方法，并帮助我们预测何时可能出现对特定抗生素的耐药性，从而允许先发制人地切换到不同的抗生素来治疗疾病。在桑格研究所，通过使用最新的DNA测序技术来分析大量的细菌突变体，我们可以首先确定细菌细胞中对生命至关重要的那些成分。这些为开发新的抗生素提供了候选靶点。其次，我们可以测量细菌细胞的每一个非必需成分对抗生素耐药性的贡献。我们已经进行了一项初步研究，该研究表明，这种方法还能告诉我们哪些细胞成分构成了细菌细胞？对抗生素敏感。这一信息告诉我们，在未来，如何可能使耐药细菌再次对抗生素敏感。它还使我们对细菌如何抵抗抗生素有了更全面的了解，并且总体上为细菌细胞成分的作用提供了线索，因为大多数成分的作用尚未完全了解，许多成分的作用尚不清楚。建议对许多致病细菌进行这些实验：对于引起伤寒的伤寒沙门菌和引起食物中毒的鼠伤寒沙门菌，已经有了所需的大量突变体收集。此外，将收集MRSA（金黄色葡萄球菌的一种）、阴沟肠杆菌和大肠杆菌的突变体，所有这些都会导致住院患者感染，对已经患有其他疾病的患者尤其危险。抗生素有很多，但种类相对较少。使用每种类型中的一种将大大减少努力和费用，最大限度地提高我们对抗生素耐药性机制的了解。一旦数据生成，它们将以一种易于理解的形式在桑格研究所的网站上公开，为研究人员和其他感兴趣的各方提供免费和广泛的资源。

Antibiotic resistance in disease-causing bacteria has spread, resulting in the inability to treat some bacterial infections, which can lead to the deaths of patients. Bacteria can become resistant to antibiotics using different mechanisms, only some of which have been characterised. A better understanding of how bacteria resist antibiotic action will assist in the making of new antibiotics, may provide new ways of controlling resistance, and help us to predict when resistance to a particular antibiotic is likely to arise, allowing a pre-emptive switch to a different antibiotic for disease treatment. At the Sanger Institute, by using the latest DNA sequencing technology to analyse very large collections of bacterial mutants, we can firstly identify those components of the bacterial cell that are essential for life. These provide candidate targets for the development of new antibiotics. Secondly, we can measure every non-essential component of the bacterial cell for its contribution to antibiotic resistance. We have performed a pilot study which has shown that the method also tells us which cellular components contribute to the bacterial cells? sensitivity to antibiotics. This information tells us how it may, in the future, be possible to make resistant bacteria susceptible once again to antibiotics. It also gives us a more complete understanding of how bacteria resist antibiotics, and in general provides clues as to the role of the bacterial cell components, as the role of most components is not fully understood and the role of many is unknown. It is proposed to perform these experiments on a number of disease causing bacteria: the large mutant collections needed are already available for Salmonella Typhi which causes typhoid fever, and Salmonella Typhimurium which causes food poisoning. In addition, mutant collections will be made in MRSA (a strain of Staphylococcus aureus), Enterobacter cloacae, and E. coli, all of which cause infections acquired by patients whilst in hospital, and are particularly dangerous for individuals who are already ill with other medical conditions. Many antibiotics exist, but there are relatively few different types. Using one of each type will maximise our understanding of antibiotic resistance mechanisms for significantly less effort and expense. Once the data have been generated, they will be made available, in an easy to understand form, on the Sanger Institute web site where they will provide a freely and widely available resource for researchers and any other interested parties.