Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da República, 2780-157 Oeiras, Portugal.
Astbury Centre for Structural Molecular Biology, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Int J Mol Sci. 2024 Jul 24;25(15):8048. doi: 10.3390/ijms25158048.
Bacteria are known to be constantly adapting to become resistant to antibiotics. Currently, efficient antibacterial compounds are still available; however, it is only a matter of time until these compounds also become inefficient. Ribonucleases are the enzymes responsible for the maturation and degradation of RNA molecules, and many of them are essential for microbial survival. Members of the PNPase and RNase II families of exoribonucleases have been implicated in virulence in many pathogens and, as such, are valid targets for the development of new antibacterials. In this paper, we describe the use of virtual high-throughput screening (vHTS) to identify chemical compounds predicted to bind to the active sites within the known structures of RNase II and PNPase from . The subsequent in vitro screening identified compounds that inhibited the activity of these exoribonucleases, with some also affecting cell viability, thereby providing proof of principle for utilizing the known structures of these enzymes in the pursuit of new antibacterials.
细菌不断适应以对抗生素产生耐药性是众所周知的。目前，仍有有效的抗菌化合物可供使用；然而，这些化合物也变得低效只是时间问题。核糖核酸酶是负责 RNA 分子成熟和降解的酶，其中许多酶对微生物的生存至关重要。外切核糖核酸酶的 PNPase 和 RNase II 家族的成员已被牵连到许多病原体的毒力中，因此，它们是开发新抗菌药物的有效靶点。在本文中，我们描述了使用虚拟高通量筛选 (vHTS) 来鉴定预测与. 中 RNase II 和 PNPase 的已知结构内的活性位点结合的化学化合物。随后的体外筛选鉴定出了抑制这些外切核糖核酸酶活性的化合物，其中一些化合物也影响细胞活力，从而为利用这些酶的已知结构来寻找新的抗菌药物提供了原理证明。
