Our limited understanding of the molecular basis for compound entry into and efflux out of Gram-negative bacteria is now recognized as a key bottleneck for the rational discovery of novel antibacterial compounds. Traditional, large-scale biochemical or target-agnostic phenotypic antibacterial screening efforts have, as a result, not been very fruitful. A main driver of this knowledge gap has been the historical lack of predictive cellular assays, tools, and models that provide structure–activity relationships to inform optimization of compound accumulation. A variety of recent approaches has recently been described to address this conundrum. This Perspective explores these approaches and considers ways in which their integration could successfully redirect antibacterial drug discovery efforts.

中文翻译：

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抗菌药物发现：需要一些组装

我们对化合物进入和流出革兰氏阴性细菌的分子基础的有限了解现在被认为是合理发现新型抗菌化合物的关键瓶颈。结果，传统的大规模生化或与目标无关的表型抗菌素筛选工作并未取得丰硕的成果。造成这种知识鸿沟的主要原因是，历史上缺乏可预测的细胞分析，工具和模型来提供结构与活性之间的关系，以优化化合物的积累。最近已经描述了各种最新的方法来解决这个难题。本观点探讨了这些方法，并考虑了它们的整合可以成功地重定向抗菌药物发现工作的方式。