Coll Francesc, Blane Beth, Bellis Katherine L, Matuszewska Marta, Wonfor Toska, Jamrozy Dorota, Toleman Michelle S, Geoghegan Joan A, Parkhill Julian, Massey Ruth C, Peacock Sharon J, Harrison Ewan M
Applied Microbial Genomics Unit, Department of Molecular Basis of Disease, Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
Nat Commun. 2025 Jan 13;16(1):302. doi: 10.1038/s41467-024-55186-x.
Staphylococcus aureus is an important human pathogen and a commensal of the human nose and skin. Survival and persistence during colonisation are likely major drivers of S. aureus evolution. Here we applied a genome-wide mutation enrichment approach to a genomic dataset of 3060 S. aureus colonization isolates from 791 individuals. Despite limited within-host genetic diversity, we observed an excess of protein-altering mutations in metabolic genes, in regulators of quorum-sensing (agrA and agrC) and in known antibiotic targets (fusA, pbp2, dfrA and ileS). We demonstrated the phenotypic effect of multiple adaptive mutations in vitro, including changes in haemolytic activity, antibiotic susceptibility, and metabolite utilisation. Nitrogen metabolism showed the strongest evidence of adaptation, with the assimilatory nitrite reductase (nasD) and urease (ureG) showing the highest mutational enrichment. We identified a nasD natural mutant with enhanced growth under urea as the sole nitrogen source. Inclusion of 4090 additional isolate genomes from 731 individuals revealed eight more genes including sasA/sraP, darA/pstA, and rsbU with signals of adaptive variation that warrant further characterisation. Our study provides a comprehensive picture of the heterogeneity of S. aureus adaptive changes during colonisation, and a robust methodological approach applicable to study in host adaptive evolution in other bacterial pathogens.
金黄色葡萄球菌是一种重要的人类病原体，也是人类鼻腔和皮肤的共生菌。在定植过程中的存活和持续存在可能是金黄色葡萄球菌进化的主要驱动力。在这里，我们对来自791名个体的3060株金黄色葡萄球菌定植分离株的基因组数据集应用了全基因组突变富集方法。尽管宿主内遗传多样性有限，但我们在代谢基因、群体感应调节因子（agrA和agrC）以及已知抗生素靶点（fusA、pbp2、dfrA和ileS）中观察到过量的蛋白质改变突变。我们在体外证明了多种适应性突变的表型效应，包括溶血活性、抗生素敏感性和代谢物利用的变化。氮代谢显示出最强的适应性证据，同化亚硝酸还原酶（nasD）和脲酶（ureG）显示出最高的突变富集。我们鉴定出一个在以尿素作为唯一氮源的条件下生长增强的nasD自然突变体。纳入来自731名个体的另外4090个分离株基因组后，又发现了另外八个具有适应性变异信号的基因，包括sasA/sraP、darA/pstA和rsbU，值得进一步研究。我们的研究全面描绘了金黄色葡萄球菌在定植过程中适应性变化的异质性，并提供了一种适用于研究其他细菌病原体宿主适应性进化的强大方法。
