A combined, chemical-microbiology approach to understand the function of novel antibiotic resistance determinant in Gram-negative bacteria.

一种化学-微生物学相结合的方法，用于了解革兰氏阴性细菌中新型抗生素耐药性决定因素的功能。

• 批准号: 2124508
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2124508
• 关键词: combined; chemical; microbiology; approach; understand

An ongoing collaboration between King's College London and Public Health England has recently identified a class of regulator proteins that may play an important role in mediating intrinsic resistance, via direct binding to particular types of antibiotic, in the important Gram-negative pathogen Klebsiella pneumoniae. We have now identified two unrelated chemical entities, but with a shared molecular target (DNA-gyrase), for which resistance appears to be mediated by this regulator. This raises the possibility that this protein is either a multidrug binding domain, capable of binding and responding to a wide range of antibiotics or is able to functionally mimic the gyrase-binding pocket. Both of these possibilities are intriguing, and we plan to use a combination of homology modelling and chemical synthesis, coupled with molecular microbiology techniques to provide tools to unpick the mechanism of action of these proteins. This family of proteins is widely distributed across a range of Gram-negative pathogens and with, some modifications to predicted domain structure, in Gram-positive pathogens also. They are also found in a number of bacteria clustered with polyketide synthase or non-ribosomal peptide synthases, where they may act as immunity proteins with, as yet, unidentified compounds. This may represent a pool of resistance determinants that impact on intrinsic susceptibility to existing and novel antibiotics. It may also represent a series of affinity ligands to be used in vitro or in vivo, that could be used to identify and characterise novel antimicrobial compounds from a variety of sources.

伦敦国王学院和英国公共卫生部门正在进行的一项合作最近发现了一类调节蛋白，它们可能通过直接结合特定类型的抗生素，在重要的革兰氏阴性病原体肺炎克雷伯菌中介导内在耐药性方面发挥重要作用。我们现在已经鉴定出两种不相关的化学实体，但具有共同的分子靶标（DNA 旋转酶），其耐药性似乎是由该调节剂介导的。这提出了一种可能性，即该蛋白质要么是多药结合结构域，能够结合并响应多种抗生素，要么能够在功能上模拟促旋酶结合袋。这两种可能性都很有趣，我们计划结合使用同源建模和化学合成，再加上分子微生物学技术来提供工具来揭示这些蛋白质的作用机制。该蛋白质家族广泛分布于一系列革兰氏阴性病原体中，并且对预测的结构域结构进行了一些修改，也存在于革兰氏阳性病原体中。它们还存在于许多与聚酮化合物合酶或非核糖体肽合酶聚集的细菌中，它们可能与尚未鉴定的化合物一起充当免疫蛋白。这可能代表了一系列影响现有和新型抗生素内在敏感性的耐药性决定因素。它还可以代表一系列在体外或体内使用的亲和配体，可用于鉴定和表征来自各种来源的新型抗菌化合物。