Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
Proc Biol Sci. 2023 Aug 30;290(2005):20231030. doi: 10.1098/rspb.2023.1030. Epub 2023 Aug 16.
The fitness effects of antibiotic resistance mutations are a major driver of resistance evolution. While the nutrient environment affects bacterial fitness, experimental studies of resistance typically measure fitness of mutants in a single environment only. We explored how the nutrient environment affected the fitness effects of rifampicin-resistant mutations in under several conditions critical for the emergence and spread of resistance-the presence of primary or secondary antibiotic, or the absence of any antibiotic. Pervasive genotype-by-environment (GxE) interactions determined fitness in all experimental conditions, with rank order of fitness in the presence and absence of antibiotics being strongly dependent on the nutrient environment. GxE interactions also affected the magnitude and direction of collateral effects of secondary antibiotics, in some cases so drastically that a mutant that was highly sensitive in one nutrient environment exhibited cross-resistance to the same antibiotic in another. It is likely that the mutant-specific impact of mutations on the global transcriptome underpins the observed GxE interactions. The pervasive, mutant-specific GxE interactions highlight the importance of doing what is rarely done when studying the evolution and spread of resistance in experimental and clinical work: assessing fitness of antibiotic-resistant mutants across a range of relevant environments.
抗生素耐药性突变的适应性效应是耐药性进化的主要驱动力。尽管营养环境会影响细菌的适应性，但针对耐药性的实验研究通常仅在单一环境中测量突变体的适应性。我们探讨了营养环境如何影响利福平耐药性突变在几种对耐药性出现和传播至关重要的条件下的适应性效应——存在主要或次要抗生素，或不存在任何抗生素。普遍存在的基因型-环境（GxE）相互作用决定了所有实验条件下的适应性，抗生素存在和不存在时的适应性顺序强烈依赖于营养环境。GxE 相互作用还影响了次要抗生素的附带效应的大小和方向，在某些情况下，一个在一种营养环境中高度敏感的突变体在另一种营养环境中对相同的抗生素表现出交叉耐药性。很可能是突变对全局转录组的特定影响导致了观察到的 GxE 相互作用。普遍存在的、突变特异性的 GxE 相互作用强调了在实验和临床工作中研究耐药性的进化和传播时很少做的事情的重要性：在一系列相关环境中评估抗生素耐药性突变体的适应性。
