摘要

      为了应对全球抗生素耐药性危机，人们研究了通过染色体突变或通过抗生素耐药基因（ARGs）水平获得的抗生素耐药性。然而，人们对两者之间的相互作用知之甚少，这可能会影响抗生素耐药性的演变。在这里，我们开发了一种多重条形码方法来评估在大肠杆菌中144个突变ARG组合在11种不同浓度的8种不同抗生素作用下的适用性。虽然大多数相互作用是中性的，但我们发现12%的突变ARG组合具有显著的相互作用。大多数精氨酸以较低的适应度成本产生高水平耐药性的能力屏蔽了低药物浓度下突变体的选择性动力学。因此，无论其抗性水平如何，高适配突变体都是经常被选择的。最后，我们确定了两个无关的耐药机制之间的强负上位性：tetA四环素耐药基因和与氨基糖苷类耐药相关的功能缺失nuo突变。我们的研究强调了一些重要的限制因素，这些因素可以更好地预测和控制抗生素耐药性的演变。

      To tackle the global antibiotic resistance crisis, antibiotic resistance acquired either vertically by chromosomal mutations or horizontally through antibiotic resistance genes (ARGs) have been studied. Yet, little is known about the interactions between the two, which may impact the evolution of antibiotic resistance. Here, we develop a multiplexed barcoded approach to assess the fitness of 144 mutant-ARG combinations in Escherichia coli subjected to eight different antibiotics at 11 different concentrations. While most interactions are neutral, we identify significant interactions for 12% of the mutant-ARG combinations. The ability of most ARGs to confer high-level resistance at a low fitness cost shields the selective dynamics of mutants at low drug concentrations. Therefore, high-fitness mutants are often selected regardless of their resistance level. Finally, we identify strong negative epistasis between two unrelated resistance mechanisms: the tetA tetracycline resistance gene and loss-of-function nuo mutations involved in aminoglycoside tolerance. Our study highlights important constraints that may allow better prediction and control of antibiotic resistance evolution.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057998/