Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Glasgow, G12 8TA, UK.
School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
Microbiology (Reading). 2022 Jul;168(7). doi: 10.1099/mic.0.001211.
The enterohemorrhagic pathotype is responsible for severe and dangerous infections in humans. Establishment of the infection requires colonization of the gastro-intestinal tract, which is dependent on the Type III Secretion System. The Type III Secretion System (T3SS) allows attachment of the pathogen to the mammalian host cell and cytoskeletal rearrangements within the host cell. Blocking the functionality of the T3SS is likely to reduce colonization and therefore limit the disease. This route offers an alternative to antibiotics, and problems with the development of antibiotics resistance. Salicylidene acylhydrazides have been shown to have an inhibitory effect on the T3SS in several pathogens. However, the main target of these compounds is still unclear. Past work has identified a number of putative protein targets of these compounds, one of which being WrbA. Whilst WrbA is considered an off-target interaction, this study presents the effect of the salicylidne acylhydrazide compounds on the activity of WrbA, along with crystal structures of WrbA from and serovar Typhimurium; the latter also containing parts of the compound in the structure. We also present data showing that the original compounds were unstable in acidic conditions, and that later compounds showed improved stability.
肠出血性血清型是导致人类严重和危险感染的原因。感染的建立需要胃肠道的定植，这依赖于 III 型分泌系统。III 型分泌系统（T3SS）允许病原体附着在哺乳动物宿主细胞上，并在宿主细胞内进行细胞骨架重排。阻断 T3SS 的功能可能会减少定植，从而限制疾病的发生。这条途径为抗生素和抗生素耐药性发展带来的问题提供了一种替代方案。水杨酰腙类化合物已被证明对几种病原体的 T3SS 具有抑制作用。然而，这些化合物的主要靶标仍不清楚。过去的工作已经确定了这些化合物的许多假定的蛋白质靶标，其中之一是 WrbA。虽然 WrbA 被认为是一种脱靶相互作用，但本研究介绍了水杨酰腙类化合物对 WrbA 活性的影响，以及来自 和 血清型鼠伤寒沙门氏菌的 WrbA 的晶体结构；后者的结构中还包含部分化合物。我们还提供了数据表明，原始化合物在酸性条件下不稳定，而后来的化合物显示出更好的稳定性。
