School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
Department of Genetics, Cell Biology & Development, College of Biological Sciences, University of Minnesota, St. Paul, Minnesota, USA.
mSphere. 2020 Jun 24;5(3):e00480-20. doi: 10.1128/mSphere.00480-20.
The importance of within-species diversity in determining the evolutionary potential of a population to evolve drug resistance or tolerance is not well understood, including in eukaryotic pathogens. To examine the influence of genetic background, we evolved replicates of 20 different clinical isolates of , a human fungal pathogen, in fluconazole, the commonly used antifungal drug. The isolates hailed from the major clades and had different initial levels of drug resistance and tolerance to the drug. The majority of replicates rapidly increased in fitness in the evolutionary environment, with the degree of improvement inversely correlated with parental strain fitness in the drug. Improvement was largely restricted to up to the evolutionary level of drug: only 4% of the evolved replicates increased resistance (MIC) above the evolutionary level of drug. Prevalent changes were altered levels of drug tolerance (slow growth of a subpopulation of cells at drug concentrations above the MIC) and increased diversity of genome size. The prevalence and predominant direction of these changes differed in a strain-specific manner, but neither correlated directly with parental fitness or improvement in fitness. Rather, low parental strain fitness was correlated with high levels of heterogeneity in fitness, tolerance, and genome size among evolved replicates. Thus, parental strain background is an important determinant in mean improvement to the evolutionary environment as well as the diversity of evolved phenotypes, and the range of possible responses of a pathogen to an antimicrobial drug cannot be captured by in-depth study of a single strain background. Antimicrobial resistance is an evolutionary phenomenon with clinical implications. We tested how replicates from diverse strains of , a prevalent human fungal pathogen, evolve in the commonly prescribed antifungal drug fluconazole. Replicates on average increased in fitness in the level of drug they were evolved to, with the least fit parental strains improving the most. Very few replicates increased resistance above the drug level they were evolved in. Notably, many replicates increased in genome size and changed in drug tolerance (a drug response where a subpopulation of cells grow slowly in high levels of drug), and variability among replicates in fitness, tolerance, and genome size was higher in strains that initially were more sensitive to the drug. Genetic background influenced the average degree of adaptation and the evolved variability of many phenotypes, highlighting that different strains from the same species may respond and adapt very differently during adaptation.
物种内多样性在决定种群进化抗性或耐受性的进化潜力方面的重要性尚未得到很好的理解，包括真核病原体。为了研究遗传背景的影响，我们在氟康唑（一种常用的抗真菌药物）中进化了 20 种不同临床分离株的复制品，这些分离株来自主要的 分支，对药物的初始耐药性和耐受性水平不同。大多数复制品在进化环境中快速增加适应性，改善程度与药物中亲本菌株的适应性呈反比。改善主要限于药物的进化水平：只有 4%的进化复制品增加了耐药性（MIC）超过药物的进化水平。普遍发生的变化是改变了药物耐受性的水平（药物浓度高于 MIC 时细胞亚群的生长缓慢）和基因组大小的多样性增加。这些变化的普遍性和主要方向在菌株特异性方面有所不同，但与亲本适应性或适应性的改善均无直接关系。相反，低亲本菌株适应性与进化复制品中适应性、耐受性和基因组大小的异质性水平较高有关。因此，亲本菌株背景是对进化环境的平均改善以及进化表型多样性的重要决定因素，而病原体对抗菌药物的可能反应范围不能通过对单一菌株背景的深入研究来捕获。抗菌药物耐药性是一种具有临床意义的进化现象。我们测试了来自流行的人类真菌病原体 的不同菌株的复制品在常用抗真菌药物氟康唑中的进化情况。在它们进化的药物水平上，复制品平均增加了适应性，适应性最差的亲本菌株提高最多。很少有复制品增加了对它们进化的药物水平以上的耐药性。值得注意的是，许多复制品增加了基因组大小并改变了药物耐受性（一种药物反应，其中细胞的一个亚群在高药物水平下生长缓慢），并且在对药物最初更敏感的菌株中，适应性、耐受性和基因组大小的复制品之间的变异性更高。遗传背景影响平均适应程度和许多表型的进化可变性，突出表明来自同一物种的不同菌株在适应过程中可能会有非常不同的反应和适应。
