| Summary: | Physiological experimentation, transcriptomics, and metabolomics were engaged to compare a fusidic acid-resistant <i>Staphylococcus aureus</i> mutant SH10001st-2 to its parent strain SH1000. SH10001st-2 harbored a mutation (H457Y) in the gene <i>fusA</i> which encodes the fusidic acid target, elongation factor G, as well as mutations in a putative phage gene of unknown function. SH10001st-2 grew slower than SH1000 at three temperatures and had reduced coagulase activity, two indicators of the fitness penalty reported for <i>fusA</i>-mediated fusidic acid- resistance in the absence of compensatory mutations. Despite the difference in growth rates, the levels of O<sub>2</sub> consumption and CO<sub>2</sub> production were comparable. Transcriptomic profiling revealed 326 genes were upregulated and 287 were downregulated in SH10001st-2 compared to SH1000. Cell envelope and transport and binding protein genes were the predominant functional categories of both upregulated and downregulated genes in SH10001st-2. Genes of virulence regulators, notably the <i>agr</i> and <i>kdp</i> systems, were highly upregulated as were genes encoding capsule production. Contrary to what is expected of mid-exponential phase cells, genes encoding secreted virulence factors were generally upregulated while those for adhesion-associated virulence factors were downregulated in SH10001st-2. Metabolomic analysis showed an overall increase in metabolite pools in SH10001st-2 compared to SH1000, mostly for amino acids and sugars. Slowed growth and metabolite accumulation may be byproducts of <i>fusA</i> mutation-mediated protein synthesis impairment, but the overall results indicate that SH10001st-2 is compensating for the H457Y fitness penalty by repurposing its virulence machinery, in conjunction with increasing metabolite uptake capacity, in order to increase nutrient acquisition.
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