Gurvic Dominik, Zachariae Ulrich
Computational Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Biochemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
NPJ Antimicrob Resist. 2024 Mar 16;2(1):6. doi: 10.1038/s44259-024-00023-w.
Gram-negative bacteria cause the majority of critically drug-resistant infections, necessitating the rapid development of new drugs with Gram-negative activity. However, drug design is hampered by the low permeability of the Gram-negative cell envelope and the function of drug efflux pumps, which extrude foreign molecules from the cell. A better understanding of the molecular determinants of compound recognition by efflux pumps is, therefore, essential. Here, we quantitatively analysed the activity of 73,737 compounds, recorded in the publicly accessible database CO-ADD, across three strains of E. coli - the wild-type, the efflux-deficient tolC variant, and the hyper-permeable lpxC variant, to elucidate the molecular principles of evading efflux pumps. We computationally investigated molecular features within this dataset that promote, or reduce, the propensity of being recognised by the TolC-dependent efflux systems in E. coli. Our results show that, alongside a range of physicochemical features, the presence or absence of specific chemical groups in the compounds substantially increases the probability of avoiding efflux. A comparison of our findings with inward permeability data further underscores the primary role of efflux in determining drug bioactivity in Gram-negative bacteria.
革兰氏阴性菌引发了大多数严重的耐药性感染，因此急需快速开发具有抗革兰氏阴性菌活性的新型药物。然而，革兰氏阴性菌的细胞壁通透性较低以及药物外排泵的功能会阻碍药物设计，这些外排泵会将外来分子排出细胞。因此，更深入了解外排泵识别化合物的分子决定因素至关重要。在此，我们对公开数据库CO-ADD中记录的73737种化合物针对三株大肠杆菌（野生型、外排缺陷型tolC变体和高通透性lpxC变体）的活性进行了定量分析，以阐明逃避外排泵的分子原理。我们通过计算研究了该数据集中促进或降低被大肠杆菌中依赖TolC的外排系统识别倾向的分子特征。我们的结果表明，除了一系列物理化学特征外，化合物中特定化学基团的存在与否会大幅增加避免被外排的概率。将我们的研究结果与内向通透性数据进行比较，进一步强调了外排在决定革兰氏阴性菌药物生物活性方面的主要作用。
