Chemical Biology Studies to Identify Potential Drug Targets in Bacteria

该项目的目的是在细菌中发现潜在的新药靶点。由于不断增加的耐药性问题，需要新的药物靶标。开发用于治疗革兰氏阴性菌的新药的主要问题之一是在细菌内获得足够的化合物暴露的挑战。这是由于两个因素，细胞包膜缺乏渗透性和存在从细胞中去除化合物的外排泵。因此，重要的是找到可以被穿透细菌的化合物抑制的靶标。命中的表征：该项目将通过针对革兰氏阴性ESKAPE病原体（E.大肠杆菌、铜绿假单胞菌、肺炎克雷伯菌和鲍曼不动杆菌）。然后，我们将通过重新购买和重新合成来验证新的命中。然后，适当的系列将进行几轮化学优化，以建立初步的结构活性关系，并进一步验证化学命中系列是特异性的。作用模式研究随后将采用经验证的化学品系列进行作用模式研究。将采用若干技术。这些技术可能包括：产生抗性，然后进行全基因组测序化学蛋白质组学，通过固定化配体的下拉实验或通过CETSA。所用技术的精确范围将取决于产生的初始数据。如果发现了潜在的靶点，则需要进一步验证。产出：人类和动物健康的潜在药物靶点。学习：学生将获得大量化学和生物学技术的培训。技能：学生将被要求进行化学合成和微生物学中的各种技术。这将适合有有机或生物化学背景的人，并且对细胞生物学有经验或兴趣。

The aim of the project will be to discover potential new drug targets in bacteria. There is a need for new drug targets due to the ever-increasing problem of drug resistance. One of the major issues with developing new drugs for treating Gram negative bacteria is the challenge of obtaining sufficient compound exposure within the bacteria. This is due to two factors, the lack of permeability of the cell envelope and the presence of efflux pumps which remove compounds from cells. Therefore it is important to find targets which can be inhibited by compounds that penetrate the bacteria.1. Characterisation of Hits:The project will initiate by screening some compound libraries against the Gram negative ESKAPE pathogens (E. coli, P. aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii). We will then validate the new hits, through re-purchase and re-synthesis. Appropriate series will then undergo several rounds of chemical optimisation to establish preliminary structure activity relationships and provide further validation that the chemical hit series are specific.2. Mode of Action StudiesMode of action studies will then be carried out with validated chemical series. A number of techniques will be followed. These could include:Resistance generation followed by whole genome sequencingChemical proteomics, either through pull-down experiments with immobilised ligands or through CETSA.The precise range of techniques used will depend on initial data generated. Where potential targets are identified, these will need further validation.Outputs: potential drug targets for both human and animal health.Learning: the student will obtain training in a large number of techniques across both chemistry and biology.Skillsets: The student will be required to carry out chemical synthesis and a variety of techniques within microbiology. This would suit someone who has a background in organic or biological chemistry and either experience or interest in cellular biology.