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The Staphylococcus aureus α-Acetolactate Synthase ALS Confers Resistance to Nitrosative Stress

ABSTRACT: Staphylococcus aureus is a worldwide pathogen that colonizes the human nasal cavity and is a major cause of respiratory and cutaneous infections. In the nasal cavity, S. aureus thrives with high concentrations of nitric oxide (NO) produced by the innate immune effectors and has available for growth slow metabolizing free hexoses, such as galactose. Here, we have used deep sequencing transcriptomic analysis (RNA-Seq) and 1H-NMR to uncover how S. aureus grown on galactose, a major carbon source present in the nasopharynx, survives the deleterious action of nitric oxide. We observed that, like on glucose, S. aureus withstands high concentrations of NO when using galactose. However, most likely this is achieved through a distinct metabolism that relies on the increased production of amino acids, such as glutamate, threonine and branched-chain amino acids. Moreover, we found that under these conditions the α-acetolactate synthase (ALS) enzyme, which converts pyruvate into α-acetolactate, plays a role in the resistance of S. aureus to NO. However, the role of ALS is not restricted to galactose but also extends to cells growing on glucose. The results suggest that ALS prevents intracellular acidification, promoting the production of branched-chain amino acids and activation of the TCA cycle. We show that ALS contributes to the successful infection of murine macrophages. Furthermore, ALS is also shown to contribute to the resistance of S. aureus to beta-lactam antibiotics such as methicillin and oxacillin.

ORGANISM(S): Staphylococcus aureus subsp. aureus USA300_FPR3757

PROVIDER: GSE99563 | GEO | 2017/06/02

SECONDARY ACCESSION(S): PRJNA388956

REPOSITORIES: GEO

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Project description:In the present study we analyzed the response of S. aureus to mupirocin, the drug of choice for nasal decolonization of S. aureus. Mupirocin selectively inhibits the bacterial isoleucyl-tRNA synthetase (IleRSs) leading to the accumulation of uncharged isoleucyl-tRNA and hence (p)ppGpp. The latter is a signal for the induction of the stringent response, an important global transcriptional and translational control mechanism that allows bacteria to adapt to nutritional deprivation. To identify proteins with an altered synthesis pattern in response to mupirocin treatment we used the highly sensitive 2-dimensional gel electrophoresis technique in combination with mass spectrometry. Obtained results were complemented by DNA-microarray, Northern blot and metabolome analysis. Whereas expression of genes involved in nucleotide biosynthesis, DNA metabolism, energy metabolism and translation was significantly down-regulated, expression of the isoleucyl-tRNA synthetase, the branched chain amino acids pathway, genes with functions in oxidative stress resistance (ahpC, katA), putative roles in stress protection (SACOL1759, SACOL2131, SACOL0815) and transport processes was increased. Of particular interest were the differences in the transcription of genes encoding virulence associated regulators (i.e. arlRS, saeRS, sarA, sarR, sarS) as well as genes directly involved in the virulence of S. aureus (i.e. fnbA, epiE, epiG, seb). In the present study we analyzed the response of S. aureus to mupirocin, the drug of choice for nasal decolonization of S. aureus. Mupirocin selectively inhibits the bacterial isoleucyl-tRNA synthetase (IleRSs) leading to the accumulation of uncharged isoleucyl-tRNA and hence (p)ppGpp. The latter is a signal for the induction of the stringent response, an important global transcriptional and translational control mechanism that allows bacteria to adapt to nutritional deprivation. In total four independent hybridization experiments with each representing a biological replicate including a control and a treated sample were carried out. To account for the dye bias two of the four replicates were dye swapped.

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The Staphylococcus aureus α-Acetolactate Synthase ALS Confers Resistance to Nitrosative Stress

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