Studies on Nucleophilic Cysteine Enzymes Involved in Bacterial Cell Wall Biosynthesis

细菌细胞壁生物合成中亲核半胱氨酸酶的研究

• 批准号: 2424823
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2424823
• 关键词: Studies; Nucleophilic; Cysteine; Enzymes; Involved

B-Lactam antibiotics are the most widely used class of antibiotics, acting through the inhibition of the bacterial cell wall synthesis. However, with increasing levels of resistance for this type of antibiotics we can no longer rely on their ability to treat common infectious diseases. L,D-transpeptidases (Ldts) are enzymes involved in bacterial cell wall synthesis that are generally not effectively inhibited by b-lactam antibiotics. The Ldts possess mostly non-essential functions, but exceptions include the M. tuberculosis LdtMt2 which is essential for virulence, and the E. faecium Ldtfm which can lead to resistance for b-lactam antibiotics. Ldts differ from other transpeptidase enzymes by employing a nucleophilic cysteine rather than a serine residue in its catalytic site. This project will involve studies on Ldts, initially focusing on LdtMt2, with a view to understanding their mechanisms and structures in detail. The project will include techniques such as MS, NMR, protein crystallography, the development of novel assays and the identification of potential Ldt inhibitors. The overall results will increase our understanding on the mechanism of cysteine enzymes and help us gain insight into the function Ldts play in bacterial survival and antibacterial resistance and may open the way to new types of inhibitors of Ldts and other classes of nucleophilic cysteine enzymes.

β-内酰胺类抗生素是最广泛使用的一类抗生素，通过抑制细菌细胞壁合成起作用。然而，随着对这类抗生素的耐药性水平不断提高，我们不能再依赖它们治疗常见传染病。L，D-转肽酶（Ldts）是参与细菌细胞壁合成的酶，通常不能被β-内酰胺抗生素有效抑制。Ldts拥有大多数非必要的功能，但例外包括M。tuberculosis LdtMt 2和E.屎肠菌Ldtfm，其可导致对b-内酰胺抗生素的耐药性。Ldts与其他转肽酶的不同之处在于在其催化位点采用亲核半胱氨酸而不是丝氨酸残基。该项目将涉及对Ldts的研究，最初侧重于LdtMt 2，以期详细了解其机制和结构。该项目将包括MS，NMR，蛋白质晶体学，新检测方法的开发和潜在Ldt抑制剂的鉴定等技术。总体结果将增加我们对半胱氨酸酶的机制的理解，并帮助我们深入了解Ldts在细菌存活和抗菌抗性中的作用，并可能为Ldts和其他类亲核半胱氨酸酶的新型抑制剂开辟道路。