Technion - Israel Institute of Technology, The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Haifa 32000, Israel +972 4 829 2590 ; +972 4 829 5703 ;
Expert Opin Drug Discov. 2010 Sep;5(9):883-902. doi: 10.1517/17460441.2010.508069. Epub 2010 Jul 21.
The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) expanded spectrum of activity and iii) reduced potential for generating bacterial resistance.
In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compounds with emphases on their potential to reduce resistance development.
Recently developed synergistic and antagonistic antibacterial drug-drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Additionally, we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances.
The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compounds are entering clinical trials. However, the key challenge in this area should be a broader experimental demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.
目前可用的抗生素不断出现且持续耐药，新抗菌药物的研发管道不畅，这迫切需要开发新的策略来解决抗菌药物耐药性日益严重的问题。一种这样的策略是开发双作用混合抗生素：将两种抑制细菌细胞中不同靶标的抗生素通过共价键链接到一个分子中。可能的好处包括：i）对抗耐药菌的活性，ii）扩大活性谱，iii）降低产生细菌耐药性的潜力。
本文详细介绍了具有不可裂解连接子的双作用混合药物设计和开发的最新进展。我们探讨了新开发的协同和拮抗混合化合物，重点是它们减少耐药性发展的潜力。
描述了最近开发的协同和拮抗抗菌药物-药物相互作用及其对抗生素耐药性进化的影响。此外，我们讨论了后者观察结果对具有协同或拮抗作用的混合抗生素开发的意义，重点是它们的协同或拮抗作用是否更有效地阻止/减少新耐药性的发展。
双作用混合抗生素的方法在克服现有耐药机制方面具有重要的当前前景，因为有三种此类化合物正在进入临床试验。然而，该领域的关键挑战应该是更广泛地实验证明开发的混合药物的“协同作用”或“拮抗作用”是否更能防止/减少耐药性的进化。在产生成功的药物之前，必须克服这一基本挑战。
