Antibiotic resistance is currently one of the most important public health problems. The golden age of antibiotic discovery ended decades ago, and new approaches are urgently needed. Therefore, preserving the efficacy of the antibiotics currently in use and developing compounds and strategies that specifically target antibiotic-resistant pathogens is critical. The identification of robust trends of antibiotic resistance evolution and of its associated trade-offs, such as collateral sensitivity or fitness costs, is invaluable for the design of rational evolution-based, ecology-based treatment approaches. In this Review, we discuss these evolutionary trade-offs and how such knowledge can aid in informing combination or alternating antibiotic therapies against bacterial infections. In addition, we discuss how targeting bacterial metabolism can enhance drug activity and impair antibiotic resistance evolution. Finally, we explore how an improved understanding of the original physiological function of antibiotic resistance determinants, which have evolved to reach clinical resistance after a process of historical contingency, may help to tackle antibiotic resistance.

抗生素耐药性是目前最重要的公共卫生问题之一。抗生素发现的黄金时代在几十年前就结束了，迫切需要新的方法。因此，保持目前使用的抗生素的功效并开发专门针对抗生素耐药病原体的化合物和策略至关重要。识别抗生素耐药性进化的强劲趋势及其相关的权衡（例如附带敏感性或适应成本）对于设计合理的基于进化、基于生态的治疗方法具有无价的价值。在这篇综述中，我们讨论了这些进化权衡，以及这些知识如何帮助指导针对细菌感染的联合或交替抗生素疗法。此外，我们还讨论了靶向细菌代谢如何增强药物活性并削弱抗生素耐药性进化。最后，我们探讨了如何更好地理解抗生素耐药性决定因素的原始生理功能，这些决定因素在经历了历史偶然过程后进化到了临床耐药性，这可能有助于解决抗生素耐药性问题。