Global Analysis of the Staphylococcus aureus Response to Mupirocin

Abstract

ABSTRACTIn the present study, we analyzed the response ofS. aureusto mupirocin, the drug of choice for nasal decolonization. Mupirocin selectively inhibits the bacterial isoleucyl-tRNA synthetase (IleRS), leading to the accumulation of uncharged isoleucyl-tRNA and eventually the synthesis of (p)ppGpp. The alarmone (p)ppGpp induces 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. The results were complemented by DNA microarray, Northern blot, and metabolome analyses. Whereas expression of genes involved in nucleotide biosynthesis, DNA metabolism, energy metabolism, and translation was significantly downregulated, expression of isoleucyl-tRNA synthetase, the branched-chain amino acid pathway, and genes with functions in oxidative-stress resistance (ahpCandkatA) and putative roles in stress protection (theyvyDhomologueSACOL0815andSACOL1759andSACOL2131) and transport processes was increased. A comparison of the regulated genes to known regulons suggests the involvement of the global regulators CodY and SigB in shaping the response ofS. aureusto mupirocin. Of particular interest was the induced transcription of genes encoding virulence-associated regulators (i.e.,arlRS,saeRS,sarA,sarR,sarS, andsigB), as well as genes directly involved in the virulence ofS. aureus(i.e.,fnbA,epiE,epiG, andseb).