摘要

在足够的浓度下，抗生素可以有效地根除许多细菌感染。然而，在治疗期间，细菌不可避免地暴露于较低的抗生素浓度，并且亚最小抑制浓度（MIC）暴露可导致多种其他效应，包括诱导毒力，这可能使治疗复杂化，或水平基因转移（HGT） ），这可以加速抗性基因的传播。细菌I型信号肽酶（SPase）是一种必需的蛋白质，其作用于一般分泌途径的最后一步。该途径是许多蛋白质分泌所必需的，包括毒力所需的许多蛋白质，而arylomycins是一类靶向SPase的天然产物抗生素。在这里，我们研究了将大肠杆菌暴露于arylomycin的亚MIC水平的后果。使用多维蛋白质鉴定技术质谱，我们发现arylomycin处理抑制许多蛋白质的适当的胞质外定位，这些蛋白质似乎是SPase底物以及几种不具有SPase底物的蛋白质。鉴定的蛋白质涉及广泛的胞质外过程并包括许多毒力因子。然后分别检查arylomycin对毒力所需的几个过程的影响，并且我们发现即使在亚MIC水平下，arylomycins也有效地抑制鞭毛，运动，生物膜形成和通过HGT传播抗生素抗性。因此，我们得出结论，arylomycins代表有希望的新疗法，具有消除感染的潜力同时减少毒力和抗性的传播。

At sufficient concentrations, antibiotics effectively eradicate many bacterial infections. However, during therapy bacteria are unavoidably exposed to lower antibiotic concentrations, and sub-minimum inhibitory concentration (MIC) exposure can result in a wide variety of other effects, including the induction of virulence, which can complicate therapy, or horizontal gene transfer (HGT), which can accelerate the spread of resistance genes. Bacterial type I signal peptidase (SPase) is an essential protein that acts at the final step of the general secretory pathway. This pathway is required for the secretion of many proteins, including many required for virulence, and the arylomycins are a class of natural product antibiotics that target SPase. Here, we investigated the consequences of exposing Escherichia coli to sub-MIC levels of an arylomycin. Using multidimensional protein identification technology mass spectrometry, we find that arylomycin treatment inhibits the proper extracytoplasmic localization of many proteins, both those that appear to be SPase substrates as well as several that do not. The identified proteins are involved in a broad range of extracytoplasmic processes and include a number of virulence factors. The effects of arylomycin on several processes required for virulence were then individually examined, and we found that even at sub-MIC levels, the arylomycins potently inhibit flagellation, motility, biofilm formation, and the dissemination of antibiotic resistance via HGT. Thus, we conclude that the arylomycins represent promising novel therapeutics with the potential to eradicate infections while simultaneously reducing virulence and the dissemination of resistance.

https://www.ncbi.nlm.nih.gov/pubmed/30420476