Using chemical modification of a novel antimicrobial drug scaffold to reduce efflux from multridrug resistant Gram-negative ESKAPE pathogens

耐多药病原体已成为公共卫生的一个主要关切，尤其令人关切的是一些革兰氏阴性病原体的出现，针对这些病原体的治疗选择越来越少，处于开发阶段的化合物也很少。这些病原体的特点是能够在接触不同的抗微生物药物后迅速发展和/或获得耐药性机制。这些病原体军械库的一个关键部分是一系列外排泵，它们有效地排除或降低细胞内大量抗生素的浓度，使病原体的耐药性显著增强。无论是从对外排泵功能的基本理解的角度来看，还是作为新型辅助治疗的靶点，这些外排泵都是相当有趣的话题。拟议的项目将使用一系列新的抗菌药物来识别抑制从细胞中移除的基团，寻找化合物的结构-功能与外排的联系。伦敦国王学院和英国公共卫生部正在进行的一项合作已经确定了一类新的化合物，它们具有抗关键革兰氏阴性病原体的活性，包括肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌。作为化学系列开发的一部分，项目团队已经确定某些化合物会受到细胞外排的影响，这被已知的外排泵抑制剂所抑制。化学系列的一些成员似乎不受外排的影响，这表明这些药物的特定修饰改变了它们作为各自外排泵底物的能力。学生将探索这一现象，旨在将化学系列中的构效关系与特定泵的外排联系起来。

Multidrug resistant pathogens have emerged as a major concern for public health and there are particular concerns about the emergence of a number of Gram-negative pathogens, for which there are dwindling treatment options and few compounds are in development stage. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens are a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, but also as targets for novel adjunct therapies. The proposed project will use a novel series of antimicrobial drugs to identify groups that inhibit removal from the cell, looking to link structure-function of the compounds with efflux.An ongoing collaboration between Kings College London and Public Health England has identified a new class of compounds with activity against key Gram-negative pathogens, including Klebsiella pneumoniae, Acinetobacter bauamnnii and Pseudomonas aeruginosa. As part of the development of the chemical series, the project team have identified that certain compounds are subject to efflux from the cell, this being inhibitable by known efflux pump inhibitors. Some members of the chemical series appear not to be subject to efflux, suggesting that the specific modifications on these drugs has altered their ability to be substrates for the respective efflux pumps. The student will explore the phenomenon, aiming to link structure-activity relationships in the chemical series with efflux by specific pumps.