Gray Declan Alan, Wenzel Michaela
Newcastle University Biosciences Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, United Kingdom.
Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
ACS Infect Dis. 2020 Jun 12;6(6):1346-1365. doi: 10.1021/acsinfecdis.0c00001. Epub 2020 Mar 19.
Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug develops even before it reaches the market. This continued resistance crisis has demonstrated that resistance to antibiotics with single protein targets develops too rapidly to be sustainable. Most successful long-established antibiotics target more than one molecule or possess targets, which are encoded by multiple genes. This realization has motivated a change in antibiotic development toward drug candidates with multiple targets. Some mechanisms of action presuppose multiple targets or at least multiple effects, such as targeting the cytoplasmic membrane or the carrier molecule bactoprenol phosphate and are therefore particularly promising. Moreover, combination therapy approaches are being developed to break antibiotic resistance or to sensitize bacteria to antibiotic action. In this Review, we provide an overview of antibacterial multitarget approaches and the mechanisms behind them.
尽管人们努力研发新型抗生素，但细菌耐药性的发展速度仍然过快，药物研发难以跟上。通常，一种新药在上市之前就会出现耐药性。这种持续的耐药危机表明，针对单一蛋白质靶点的抗生素耐药性发展过快，难以持续。大多数长期以来成功的抗生素靶向多个分子或拥有由多个基因编码的靶点。这一认识促使抗生素研发转向具有多个靶点的候选药物。一些作用机制预先假定有多个靶点或至少有多种效应，例如靶向细胞质膜或载体分子磷酸细菌萜醇，因此特别有前景。此外，正在开发联合治疗方法以克服抗生素耐药性或使细菌对抗生素作用敏感。在本综述中，我们概述了抗菌多靶点方法及其背后的机制。
