Department of Genetics, Faculty of Biology, Sofia University "St. Kliment Ohridski", 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria.
ACS Synth Biol. 2022 May 20;11(5):1845-1855. doi: 10.1021/acssynbio.2c00013. Epub 2022 Apr 20.
In the past several decades, antibiotic drug resistance has emerged as a significant challenge in modern medicine due to the rise of many bacterial pathogenic strains resistant to all known antibiotics. At the same time, riboswitches have emerged as novel targets for antibacterial drug discovery. Here for the first time, we describe the design and applications of antisense oligonucleotides as antibacterial agents that target a riboswitch. The antisense oligonucleotides are covalently coupled with two different cell-penetrating peptides, penetrating Gram-positive and Gram-negative bacterial cells. We specifically target Flavin MonoNucleotide (FMN) riboswitches in , , and that control both synthesis and import of FMN precursors. We have established an average antibiotic dosage by antisense oligonucleotides that inhibit 80% of bacterial growth at 700 nM (4.5 μg/mL). Furthermore, the antisense oligonucleotides do not exhibit toxicity in human cell lines at this concentration. The results demonstrate that riboswitches are suitable targets in antisense technology for antibacterial drug development.
在过去的几十年中，由于许多对抗生素具有耐药性的细菌病原体的出现，抗生素药物耐药性已成为现代医学的重大挑战。与此同时，核糖开关已成为抗菌药物发现的新靶标。在这里，我们首次描述了反义寡核苷酸作为针对核糖开关的抗菌剂的设计和应用。反义寡核苷酸与两种不同的穿透肽共价连接，穿透革兰氏阳性和革兰氏阴性细菌细胞。我们特别针对 、 和 中的黄素单核苷酸 (FMN) 核糖开关，这些核糖开关控制 FMN 前体的合成和导入。我们已经确定了一个平均抗生素剂量，即反义寡核苷酸抑制 700 nM（4.5 μg/mL）时 80%的细菌生长。此外，在该浓度下，反义寡核苷酸在人细胞系中没有表现出毒性。结果表明，核糖开关是用于抗菌药物开发的反义技术中的合适靶标。
