Hunan Key Laboratory for Super Microstructure and Ultrafast Process, School of Physics and Electronics Central South University, Changsha 410083, China.
Department of Clinical Laboratory, Xiangya Hospital of Central South University, Changsha 410008, China.
Curr Med Chem. 2021;28(6):1104-1125. doi: 10.2174/0929867327666200602132504.
The emergence of antibiotic-resistant bacteria and the slow progress in searching for new antimicrobial agents makes it hard to treat bacterial infections and cause problems for the healthcare system worldwide, including high costs, prolonged hospitalizations, and increased mortality. Therefore, the discovery of effective antibacterial agents is of great importance. One attractive alternative is antisense peptide nucleic acid (PNA), which inhibits or eliminates gene expression by binding to the complementary messenger RNA (mRNA) sequence of essential genes or the accessible and functionally important regions of the ribosomal RNA (rRNA). Following 30 years of development, PNAs have played an extremely important role in the treatment of Gram-positive, Gram-negative, and acidfast bacteria due to their desirable stability of hybrid complex with target RNA, the strong affinity for target mRNA/rRNA, and the stability against nucleases. PNA-based antisense antibiotics can strongly inhibit the growth of pathogenic and antibiotic-resistant bacteria in a sequence-specific and dose-dependent manner at micromolar concentrations. However, several fundamental challenges, such as intracellular delivery, solubility, physiological stability, and clearance still need to be addressed before PNAs become broadly applicable in clinical settings. In this review, we summarize the recent advances in PNAs as antibacterial agents and the challenges that need to be overcome in the future.
抗生素耐药菌的出现以及新抗菌药物研发进展缓慢，使得细菌感染的治疗变得困难，并给全球医疗保健系统带来了诸多问题，包括高昂的成本、延长的住院时间和增加的死亡率。因此，发现有效的抗菌剂非常重要。一种有吸引力的替代品是反义肽核酸（PNA），它通过与必需基因的互补信使 RNA（mRNA）序列或核糖体 RNA（rRNA）的可及和功能重要区域结合来抑制或消除基因表达。经过 30 年的发展，由于其与靶 RNA 杂交复合物的理想稳定性、对靶 mRNA/rRNA 的强亲和力以及对核酸酶的稳定性，PNAs 在治疗革兰氏阳性、革兰氏阴性和抗酸菌方面发挥了极其重要的作用。基于 PNA 的反义抗生素可以在毫摩尔浓度下以序列特异性和剂量依赖性方式强烈抑制致病性和耐药菌的生长。然而，在 PNA 广泛应用于临床之前，仍需要解决几个基本挑战，如细胞内递送、溶解性、生理稳定性和清除率。在这篇综述中，我们总结了 PNA 作为抗菌剂的最新进展以及未来需要克服的挑战。
