ABSTRACT

Introduction: Making selective inhibitors of novel Gram-negative targets is not a substantial challenge – getting them into Gram-negative bacteria to reach their lethal target is the bottleneck. Poor permeability of the antibiotic requires high concentration causing off target activity. The lack of simple experimental techniques to measure antibiotic uptake as well as the local concentration at the target site creates a particular bottleneck in understanding and in improving the antibiotic activity.

Areas covered: Here we recall current approaches to quantify the uptake. For a few antibiotics with known evidence for channel-limited permeation, the flux across a single OmpF or OmpC channel has been measured. For a typical concentration gradient of 1 µM of antibiotics the uptake varies between one up to few hundred molecules per second and per channel.

Expert opinion: The current research effort is on quantifying the flux for a larger list of compounds on a cellular (mass spectra, fluorescence) or at single channel level (electrophysiology). A larger dataset of single channel permeabilities under various condition will be a powerful tool for understanding and improving the activity of antibiotics.

摘要

简介：选择性抑制新型革兰氏阴性目标的抑制剂并不是一个实质性的挑战-使它们进入革兰氏阴性细菌以达到其致命目标是瓶颈。抗生素的渗透性差需要高浓度，从而导致脱靶活性。缺乏测量抗生素吸收以及目标部位局部浓度的简单实验技术，这在理解和改善抗生素活性方面造成了特别的瓶颈。

涵盖的领域：在这里，我们回顾当前量化摄取量的方法。对于一些已知的通道受限渗透证据的抗生素，已测量了跨单个OmpF或OmpC通道的通量。对于典型的1 µM抗生素浓度梯度，每秒和每个通道的摄取量在一个至几百个分子之间变化。

专家意见：当前的研究工作是在细胞（质谱，荧光）或单通道水平（电生理学）上对大量化合物的通量进行定量分析。在各种条件下，较大的单通道渗透性数据集将成为了解和改善抗生素活性的有力工具。