Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California, USA.
Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, California, USA.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.01990-20.
Epistasis influences the gene-environment interactions that shape bacterial fitness through antibiotic exposure, which can ultimately affect the availability of certain resistance phenotypes to bacteria. The substitutions present within confer both cephalosporin and β-lactamase inhibitor resistance. We wanted to compare the evolution of with that of another variant, , which differs in that contains only substitutions that contribute to cephalosporin resistance. Differences between the landscapes and epistatic interactions of these TEM variants are important for understanding their separate evolutionary responses to antibiotics. We hypothesized the substitutions within would result in more epistatic interactions than for As expected, we found more epistatic interactions between the substitutions present in than in Our results suggest that selection from many cephalosporins is required to achieve the full potential resistance to cephalosporins but that a single β-lactam and inhibitor combination will drive evolution of the full potential resistance phenotype. Surprisingly, we also found significantly positive increases in growth rates as antibiotic concentration increased for some of the strains expressing precursor genotypes but not the variants. This result further suggests that additive interactions more effectively optimize phenotypes than epistatic interactions, which means that exposure to numerous cephalosporins actually increases the ability of a TEM enzyme to confer resistance to any single cephalosporin.
上位性影响通过抗生素暴露形成的基因-环境相互作用，从而影响细菌对特定耐药表型的适应性。 赋予头孢菌素和β-内酰胺酶抑制剂耐药性。 我们想比较 和另一个变体 的进化， 仅包含导致头孢菌素耐药性的取代。 这些 TEM 变体之间景观和上位性相互作用的差异对于理解它们对抗生素的单独进化反应很重要。 我们假设 中的取代将产生比 更多的上位性相互作用。 正如预期的那样，我们发现 中存在的取代之间的上位性相互作用比 中多。 我们的结果表明，需要从许多头孢菌素中选择才能实现对头孢菌素的全部潜在耐药性，但单一β-内酰胺和抑制剂组合将驱动全部潜在耐药表型的进化。 令人惊讶的是，我们还发现一些表达 前体基因型的菌株在抗生素浓度增加时，其增长率呈显著正增长，但 变体则没有。 这一结果进一步表明，加性相互作用比上位性相互作用更有效地优化表型，这意味着暴露于许多头孢菌素实际上增加了 TEM 酶赋予对任何单一头孢菌素的耐药性的能力。
