Data from: Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas

Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across 8 strains that span the diversity of the genus Pseudomonas. We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across 3 strains of Pseudomonas. Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.

抗生素耐药性通常由必需基因保守位点的突变演化产生，该过程会在亲缘关系较远的细菌菌株与物种间引发平行分子进化。然而，此类耐药突变对不同细菌类群的适合度是否存在平行效应，目前仍不明确。这是一个亟需解决的关键问题，因为耐药突变的适合度效应在病原菌种群耐药性的传播与维持中扮演核心角色。本研究针对这一问题展开探究：我们选取覆盖假单胞菌属（Pseudomonas）全部多样性类群的8株菌株，检测其RNA聚合酶β亚基（rpoB）基因上一系列利福平耐药突变的适合度效应。结果显示，近50%的rpoB突变存在背景依赖性适合度代价，这表明rpoB与基因组其余部分之间的上位性相互作用十分普遍。此外，上位性通常作用强烈，且是决定耐药突变代价的主导遗传因素。为探究上位性的功能基础，同时考虑到rpoB在转录过程中的核心地位，我们进一步检测了常见rpoB突变对3株假单胞菌转录效率的影响。研究发现，转录效率与不同菌株的适合度呈显著相关，而上位性的产生机制在于：单个rpoB突变在不同遗传背景下，对转录效率的影响存在差异。