We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addition to active drug efflux, making this cell envelope impermeable to most compounds. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate Gram-negative bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chemical space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective analysis of chemical libraries for the ability of compounds to accumulate in Gram-negative bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-negative permeation and efflux, which can then be used to guide medicinal chemistry campaigns and the design of antibacterial discovery libraries.

我们生活在抗生素耐药性的时代，如果不出现新的解决方案，这个问题将会逐渐恶化。特别是，革兰氏阴性病原体带来了生物和化学挑战，阻碍了新抗菌药物的发现。首先，除了活性药物外流外，这些细菌还受到由两层具有不同渗透特性的膜组成的低渗透性屏障的保护，免受各种结构不同的药物的侵害，从而使该细胞包膜对大多数化合物都是不可渗透的。其次，目前用于药物发现的化学库几乎不含能够穿透革兰氏阴性细菌的化合物。由于这些挑战，密集的筛选活动几乎没有取得成功，这凸显了需要新的方法来识别与抗菌药物发现特别相关的化学空间区域。在此，我们概述了对该问题的新见解，并概述了使用化学库的前瞻性分析来解决该问题的一般方法，以了解化合物在革兰氏阴性细菌中积累的能力。总体目标是开发强大的化学信息学工具来预测革兰氏阴性渗透和流出，然后可用于指导药物化学活动和抗菌发现库的设计。