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<p><i>Staphylococcus aureus</i> is an important human pathogen and a commensal of the human nose and skin. Survival and persistence during colonisation are likely major drivers of <i>S. aureus</i> evolution. Here we applied a genome-wide mutation enrichment approach to a genomic dataset of 3060 <i>S. aureus</i> 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 (<i>agrA</i> and <i>agrC</i>) and in known antibiotic targets (<i>fusA</i>, <i>pbp2</i>, <i>dfrA</i> and <i>ileS</i>). 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 (<i>nasD</i>) and urease (<i>ureG</i>) showing the highest mutational enrichment. We identified a <i>nasD</i> 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 <i>sasA</i>/<i>sraP</i>, <i>darA/pstA</i>, and <i>rsbU</i> with signals of adaptive variation that warrant further characterisation. Our study provides a comprehensive picture of the heterogeneity of <i>S. aureus</i> adaptive changes during colonisation, and a robust methodological approach applicable to study <i>in host</i> adaptive evolution in other bacterial pathogens.</p>

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The mutational landscape of Staphylococcus aureus during colonisation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月13日

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  • Francesc Coll,
  • Beth Blane,
  • Katherine L. Bellis,
  • Marta Matuszewska,
  • Toska Wonfor,
  • Dorota Jamrozy,
  • Michelle S. Toleman,
  • Joan A. Geoghegan,
  • Julian Parkhill,
  • Ruth C. Massey,
  • Sharon J. Peacock,
  • Ewan M. Harrison

摘要

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.