Teichmann Lisa, Pasman Raymond, Luitwieler Sam, Varriale Chiara, Bengtsson-Palme Johan, Ter Kuile Benno
University of Amsterdam, Swammerdam Institute of Life Sciences, Molecular Biology and Microbial Food Safety, Amsterdam, The Netherlands.
Department of Life Sciences, SciLifeLab, Division of Systems and Synthetic Biology, Chalmers University of Technology, Gothenburg, Sweden; Department of Infectious Diseases, University of Gothenburg, Institute of Biomedicine, Gothenburg, Sweden; Centre for Antibiotic Resistance Research (CARe), Gothenburg, Sweden.
Int J Antimicrob Agents. 2025 Feb;65(2):107420. doi: 10.1016/j.ijantimicag.2024.107420. Epub 2024 Dec 30.
Antibiotic resistance is a growing global healthcare challenge, treatment of bacterial infections with fluoroquinolones being no exception. These antibiotics can induce genetic instability through several mechanisms, one of the most significant being the activation of the SOS response. During exposure to sublethal concentration, this stress response increases mutation rates, accelerating resistance evolution.
To explore the role of the SOS response in fluoroquinolone adaptation, we induced de novo resistance by exposure to step-wise increasing concentrations Escherichia coli wild-type (MG1655) and a ΔrecA mutant strain, which is deficient in SOS activation. Both strains were exposed to stepwise increasing concentrations of ciprofloxacin and enrofloxacin - two fluoroquinolones that differ only by a single methyl group.
Development of resistance against both fluoroquinolones was severely hampered in the ΔrecA mutant. While these antibiotics are often assumed to elicit similar cellular responses, our data revealed distinct genomic and adaptive differences. Building on these findings, we performed a comparative proteomics analysis to investigate how E. coli adapts to ciprofloxacin and enrofloxacin at the protein level.
The results demonstrate that the slight structural variation between ciprofloxacin and enrofloxacin leads to unique proteomic adaptations. These findings suggest that even subtle chemical differences can lead to distinct adaptive trajectories and illustrate the flexibility of cellular stress responses.
抗生素耐药性是全球日益严峻的医疗挑战，使用氟喹诺酮类药物治疗细菌感染也不例外。这些抗生素可通过多种机制诱导基因不稳定，其中最重要的机制之一是激活SOS反应。在暴露于亚致死浓度期间，这种应激反应会增加突变率，加速耐药性进化。
为了探究SOS反应在氟喹诺酮适应性中的作用，我们通过逐步增加浓度的方式，使野生型大肠杆菌（MG1655）和缺乏SOS激活能力的ΔrecA突变菌株产生从头耐药性。这两种菌株都逐步暴露于环丙沙星和恩诺沙星（两种仅相差一个甲基的氟喹诺酮类药物）浓度增加的环境中。
ΔrecA突变体对这两种氟喹诺酮类药物的耐药性发展受到严重阻碍。虽然通常认为这些抗生素会引发相似的细胞反应，但我们的数据揭示了明显的基因组和适应性差异。基于这些发现，我们进行了一项比较蛋白质组学分析，以研究大肠杆菌在蛋白质水平上如何适应环丙沙星和恩诺沙星。
结果表明，环丙沙星和恩诺沙星之间的微小结构差异导致了独特的蛋白质组适应性。这些发现表明，即使是细微的化学差异也可能导致不同的适应性轨迹，并说明了细胞应激反应的灵活性。
