School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
Centre for Research and Innovation, Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas (UPC), Lima 15023, Peru, Italy.
Curr Top Med Chem. 2018;18(24):2080-2096. doi: 10.2174/1568026618666181025092546.
The use of antibiotics has revolutionized medicine, greatly improving our capacity to save millions of lives from otherwise deadly bacterial infections. Unfortunately, the health-associated benefits provided by antibiotics have been counteracted by bacteria developing or acquiring resistance mechanisms. The negative impact to public health is now considered of high risk due to the rapid spreading of multi-resistant strains. More than 60 % of clinically relevant antibiotics of natural origin target the ribosome, the supramolecular enzyme which translates the genetic information into proteins. Although many of these antibiotics bind the small ribosomal subunit, only a few are reported to inhibit the initiation of protein synthesis, with none reaching commercial availability. Counterintuitively, translation initiation is the most divergent phase of protein synthesis between prokaryotes and eukaryotes, a fact which is a solid premise for the successful identification of drugs with reduced probability of undesired effects to the host. Such a paradox is one of its kind and deserves special attention. In this review, we explore the inhibitors that bind the 30S ribosomal subunit focusing on both the compounds with proved effects on the translation initiation step and the underreported translation initiation inhibitors. In addition, we explore recent screening tests and approaches to discover new drugs targeting translation.
抗生素的使用彻底改变了医学，大大提高了我们拯救数以百万计的生命的能力，否则这些生命将死于致命的细菌感染。不幸的是，由于多耐药株的迅速传播，抗生素所带来的健康相关益处被细菌产生或获得耐药机制所抵消。这种负面影响现在被认为对公众健康具有高风险，因为抗生素是治疗细菌感染的主要药物之一，如果不能有效治疗，可能会导致严重的疾病甚至死亡。
超过 60%的临床相关天然来源抗生素靶向核糖体，核糖体是将遗传信息翻译成蛋白质的超分子酶。尽管许多这些抗生素结合小核糖体亚基，但只有少数被报道抑制蛋白质合成的起始，没有一种达到商业可用性。反直觉的是，翻译起始是原核生物和真核生物之间蛋白质合成最具差异的阶段，这一事实是成功鉴定具有降低对宿主产生不良影响概率的药物的坚实前提。这种悖论是独一无二的，值得特别关注。在这篇综述中，我们探讨了结合 30S 核糖体亚基的抑制剂，重点关注已证明对翻译起始步骤有影响的化合物以及报道较少的翻译起始抑制剂。此外，我们还探讨了最近发现针对翻译的新药的筛选测试和方法。
