Allen Richard C, Pfrunder-Cardozo Katia R, Hall Alex R
Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland.
mSystems. 2021 Dec 21;6(6):e0105521. doi: 10.1128/mSystems.01055-21. Epub 2021 Nov 30.
Mutations conferring resistance to one antibiotic can increase (cross-resistance) or decrease (collateral sensitivity) resistance to others. Antibiotic combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants of Escherichia coli using five antibiotics, before measuring collateral effects on resistance to other paired antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, and bile). This revealed that local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favoring different sets of mutants (with different collateral sensitivities) and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications. When bacteria become resistant to an antibiotic, the genetic changes involved sometimes increase (cross-resistance) or decrease (collateral sensitivity) their resistance to other antibiotics. Antibiotic combinations showing repeatable collateral sensitivity could be used in treatment to slow resistance evolution. However, collateral sensitivity interactions may depend on the local environmental conditions that bacteria experience, potentially reducing repeatability and clinical application. Here, we show that variation in local conditions (pH, temperature, and bile salts) can influence collateral sensitivity in two ways: by favoring different sets of mutants during bacterial resistance evolution (with different collateral sensitivities to other antibiotics) and by modifying expression of collateral effects for individual mutants. This suggests that translation from the lab to the clinic of new approaches exploiting collateral sensitivity will be influenced by local abiotic conditions.
赋予对一种抗生素耐药性的突变可能会增加（交叉耐药性）或降低（协同敏感性）对其他抗生素的耐药性。表现出协同敏感性的抗生素组合可用于减缓耐药性演变的治疗。然而，从实验室到临床的转化需要了解协同效应在不同环境条件下是否稳定。在这里，我们使用五种抗生素分离并鉴定了大肠杆菌的耐药突变体，然后测量了对其他配对抗生素耐药性的协同效应。在分离和表型分析过程中，我们以与自然相关的方式改变条件（pH值、温度和胆汁）。这表明局部非生物条件改变了对分离过程中使用的抗生素和其他抗生素的耐药性表达。因此，局部条件通过两种方式影响协同敏感性：通过支持不同的突变体集合（具有不同的协同敏感性）以及通过改变单个突变体的协同效应表达。这些结果将协同敏感性置于环境变化的背景下，对转化为实际应用具有重要意义。当细菌对一种抗生素产生耐药性时，所涉及的基因变化有时会增加（交叉耐药性）或降低（协同敏感性）它们对其他抗生素的耐药性。显示出可重复协同敏感性的抗生素组合可用于治疗以减缓耐药性演变。然而，协同敏感性相互作用可能取决于细菌所经历的局部环境条件，这可能会降低可重复性和临床应用价值。在这里，我们表明局部条件（pH值、温度和胆盐）的变化可以通过两种方式影响协同敏感性：在细菌耐药性演变过程中支持不同的突变体集合（对其他抗生素具有不同的协同敏感性）以及通过改变单个突变体的协同效应表达。这表明利用协同敏感性的新方法从实验室到临床的转化将受到局部非生物条件的影响。
