Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
Chem Rev. 2021 Mar 24;121(6):3464-3494. doi: 10.1021/acs.chemrev.0c01214. Epub 2021 Feb 19.
The use of life-saving antibiotics has long been plagued by the ability of pathogenic bacteria to acquire and develop an array of antibiotic resistance mechanisms. The sum of these resistance mechanisms, the antibiotic resistome, is a formidable threat to antibiotic discovery, development, and use. The study and understanding of the molecular mechanisms in the resistome provide the basis for traditional approaches to combat resistance, including semisynthetic modification of naturally occurring antibiotic scaffolds, the development of adjuvant therapies that overcome resistance mechanisms, and the total synthesis of new antibiotics and their analogues. Using two major classes of antibiotics, the aminoglycosides and tetracyclines as case studies, we review the success and limitations of these strategies when used to combat the many forms of resistance that have emerged toward natural product-based antibiotics specifically. Furthermore, we discuss the use of the resistome as a guide for the genomics-driven discovery of novel antimicrobials, which are essential to combat the growing number of emerging pathogens that are resistant to even the newest approved therapies.
长期以来，挽救生命的抗生素的使用一直受到致病菌获取和发展一系列抗生素耐药机制的能力的困扰。这些耐药机制的总和，即抗生素耐药组，是对抗生素发现、开发和使用的巨大威胁。耐药组中分子机制的研究和理解为传统的耐药性防治方法提供了基础，包括对天然存在的抗生素支架进行半合成修饰、开发克服耐药机制的辅助疗法，以及新抗生素及其类似物的全合成。我们使用氨基糖苷类和四环素类这两类主要抗生素作为案例研究，综述了这些策略在对抗针对天然产物抗生素的多种耐药形式时的成功和局限性。此外，我们还讨论了将耐药组用作指导，通过基因组学发现新型抗菌药物，这对于对抗甚至对最新批准的治疗方法都具有耐药性的越来越多的新型病原体至关重要。
