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Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?
Medicinal Research Reviews ( IF 10.9 ) Pub Date : 2016-09-30 , DOI: 10.1002/med.21417
Sandhya Bansal 1 , Priyanka Bajaj 2 , Stuti Pandey 3 , Vibha Tandon 2, 3
Affiliation  

DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis‐à‐vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase‐targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.

中文翻译:

拓扑异构酶:抗性与敏感性,我们能走多远?

DNA拓扑异构酶无处不在,是一种出色的分子机器,可帮助改变活细胞中DNA的拓扑结构。这些核酸酶在DNA复制,转录和重组过程中起着至关重要的作用,而不同物种之间的序列相似性较低,这使得拓扑异构酶成为不同抗癌和抗菌药物的独特且有吸引力的靶标。然而,由于以相应基因的突变为主导的抗性发展,现有的分子类别对拓扑异构酶的可药用性正变得越来越可质疑。当前面临新分子发展下降的情况还包括一个可能挑战拓扑异构酶靶向治疗的重要因素。因此,当务之急是明智地使用现有的抑制剂,以免迅速失去对目标的控制力,我们可能不会走得太远。此外,重要的是不仅设计新的分子,而且开发新的方法来避免由于多重抗性机制而在治疗中产生障碍的方法也很重要。这篇综述简要介绍了不同种类的拓扑异构酶抑制剂,重点研究了拓扑异构酶突变引起的耐药性,并讨论了各种增加拓扑异构酶抑制剂功效的方法。在后面的部分中,我们还建议使用双苯并咪唑类与外排泵抑制剂一起产生协同杀菌作用的可能性。重要的是,不仅要设计新的分子,而且要开发出可以避免由于多重耐药机制而导致治疗障碍的新方法。这篇综述简要介绍了不同种类的拓扑异构酶抑制剂,重点研究了拓扑异构酶突变引起的耐药性,并讨论了各种增加拓扑异构酶抑制剂功效的方法。在后面的部分中,我们还建议使用双苯并咪唑类与外排泵抑制剂一起产生协同杀菌作用的可能性。重要的是,不仅要设计新的分子,而且要开发出可以避免由于多重耐药机制而导致治疗障碍的新方法。这篇综述简要介绍了不同种类的拓扑异构酶抑制剂,重点研究了拓扑异构酶突变引起的耐药性,并讨论了各种增加拓扑异构酶抑制剂功效的方法。在后面的部分中,我们还建议使用双苯并咪唑类与外排泵抑制剂一起产生协同杀菌作用的可能性。
更新日期:2016-09-30
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