Pavlova Nikolet, Traykovska Martina, Penchovsky Robert
Laboratory of Synthetic Biology and Bioinformatics, Faculty of Biology, Sofia University "St. Kliment Ohridski", 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria.
Antibiotics (Basel). 2023 Nov 8;12(11):1607. doi: 10.3390/antibiotics12111607.
Antimicrobial drug resistance has emerged as a significant challenge in contemporary medicine due to the proliferation of numerous bacterial strains resistant to all existing antibiotics. Meanwhile, riboswitches have emerged as promising targets for discovering antibacterial drugs. Riboswitches are regulatory elements in certain bacterial mRNAs that can bind to specific molecules and control gene expression via transcriptional termination, prevention of translation, or mRNA destabilization. By targeting riboswitches, we aim to develop innovative strategies to combat antibiotic-resistant bacteria and enhance the efficacy of antibacterial treatments. This convergence of challenges and opportunities underscores the ongoing quest to revolutionize medical approaches against evolving bacterial threats. For the first time, this innovative review describes the rational design and applications of chimeric antisense oligonucleotides as antibacterial agents targeting four riboswitches selected based on genome-wide bioinformatic analyses. The antisense oligonucleotides are coupled with the cell-penetrating oligopeptide pVEC, which penetrates Gram-positive and Gram-negative bacteria and specifically targets glmS, FMN, TPP, and SAM-I riboswitches in , , and . The average antibiotic dosage of antisense oligonucleotides that inhibits 80% of bacterial growth is around 700 nM (4.5 μg/mL). Antisense oligonucleotides do not exhibit toxicity in human cell lines at this concentration. The results demonstrate that these riboswitches are suitable targets for antibacterial drug development using antisense oligonucleotide technology. The approach is fully rational because selecting suitable riboswitch targets and designing ASOs that target them are based on predefined criteria. The approach can be used to develop narrow or broad-spectrum antibiotics against multidrug-resistant bacterial strains for a short time. The approach is easily adaptive to new resistance using targeting NGS technology.
由于对所有现有抗生素均具有抗性的众多细菌菌株的扩散，抗菌药物耐药性已成为当代医学中的一项重大挑战。与此同时，核糖开关已成为发现抗菌药物的有前景的靶点。核糖开关是某些细菌信使核糖核酸（mRNA）中的调控元件，可与特定分子结合，并通过转录终止、阻止翻译或使mRNA不稳定来控制基因表达。通过靶向核糖开关，我们旨在开发创新策略来对抗抗生素耐药细菌，并提高抗菌治疗的疗效。这种挑战与机遇的交汇凸显了人们持续不断地寻求革新针对不断演变的细菌威胁的医学方法。本创新性综述首次描述了嵌合反义寡核苷酸作为靶向基于全基因组生物信息学分析选择的四种核糖开关的抗菌剂的合理设计与应用。反义寡核苷酸与细胞穿透寡肽pVEC偶联，pVEC可穿透革兰氏阳性菌和革兰氏阴性菌，并特异性靶向枯草芽孢杆菌、大肠杆菌和粪肠球菌中的glmS、FMN、TPP和SAM-I核糖开关。抑制80%细菌生长的反义寡核苷酸的平均抗生素剂量约为700 nM（4.5 μg/mL）。在此浓度下，反义寡核苷酸在人细胞系中未表现出毒性。结果表明，这些核糖开关是使用反义寡核苷酸技术开发抗菌药物的合适靶点。该方法完全合理，因为选择合适的核糖开关靶点并设计靶向它们的反义寡核苷酸是基于预定义的标准。该方法可用于在短时间内开发针对多重耐药细菌菌株的窄谱或广谱抗生素。该方法利用靶向下一代测序（NGS）技术很容易适应新出现的耐药性。
