Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance.

尽管代谢在抗生素致死率中起积极作用，但抗生素耐药性通常与药物靶标修饰、酶失活和/或转运有关，而不是与代谢过程有关。大肠杆菌的进化实验依赖于生长依赖性选择，这可能对抗生素耐药性情况提供有限的看法。我们对大肠杆菌进行了测序和分析适应于代谢状态越来越高的代表性抗生素。这揭示了各种未被充分认识的非经典基因，例如与中心碳和能量代谢相关的基因，这些基因与抗生素耐药性有关。这些代谢改变导致基础呼吸降低，从而阻止了抗生素介导的三羧酸循环活动的诱导，从而避免了代谢毒性并最大限度地降低了药物致死率。在超过 3500 种临床大肠杆菌病原体的基因组中，一些已识别的代谢特异性突变过多，表明具有临床相关性。