Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy.

已经提出了几种基于组合或循环不同抗生素的有希望的策略来提高疗效和抵消耐药性演变，但我们仍然缺乏对抗生素相互作用的生理反应和遗传机制以及这些策略的临床适用性的深入了解。在暴露于抗生素的细菌中，生理应激反应和新出现的抗性突变（发生在不同的时间尺度）的综合影响会产生复杂且通常不可预测的动态。在这篇综述中，我们介绍了我们目前对细菌细胞生理学和抗生素反应遗传学的理解。我们强调最近发现的协同和拮抗药物相互作用机制，由微生物生理学引起的抗生素之间的时间相互作用滞后，以及抗生素与耐药性突变之间的相互作用，可导致侧支敏感性或交叉耐药性。我们讨论了不同现象之间可能的联系并指出了相关的研究方向。对药物和遗传相互作用的更好和更统一的理解可能会推动抗生素治疗。