Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Whole-transcriptome analysis of Staphylococcus aureus under laboratory and infection-mimicking conditions

ABSTRACT: We report the condition-dependent transcriptome of S. aureus HG001, a derivative of strain NCTC 8325, by strand-specific tiling array hybridizations. More than 40 experimental conditions were investigated ranging from optimal in vitro growth to interaction with host cells. Analyses included the systematic mapping of transcription units, annotation of non-coding RNAs, the classification of promoters according to their dependency on SigA and SigB, and the prediction of potentially new transcription factor target sites. Antisense RNAs being of particular interest because of the small number of alternative sigma factors used by S. aureus were found to be relatively rare, overlapping only 6% of the annotated coding genes. RNA samples prepared from S. aureus HG001 grown in shake flask or cell culture infection experiments were reverse transcribed, labeled and hybridized to tiling arrays. Hybridizations were performed in triplicate using RNA isolated from independent cultures.

ORGANISM(S): Staphylococcus aureus

SUBMITTER: Pierre Nicolas

PROVIDER: E-GEOD-70040 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Subinhibitory concentrations of the neuroleptic drug thioridazine (TDZ) are well-known to enhance the killing of methicillin-resistant S. aureus (MRSA) by Î²-lactam antibiotics, however, the mechanism underlying the synergy between TDZ and Î²-lactams is not fully understood. In the present study we have examined the effect of a subinhibitory concentration of TDZ on antimicrobial resistance, the global transcriptome, and the cell wall composition of MRSA USA300. We show that TDZ is able to sensitize the bacteria to several classes of antimicrobials targeting the late stages of peptidoglycan synthesis. Furthermore, our microarray analysis demonstrates that TDZ modulates the expression of genes encoding membrane and surface proteins, transporters, and enzymes involved in amino acid biosynthesis. Interestingly, resemblance between the transcriptional profile of TDZ treatment and the transcriptomic response of S. aureus to known inhibitors of cell wall synthesis suggests that TDZ disturbs peptidoglycan biosynthesis at a stage that precedes transpeptidation. In support of this notion, dramatic changes in the muropeptide profile of USA300 were observed following growth in the presence of TDZ, indicating that TDZ can interfere with the formation of the pentaglycine branches. Strikingly, the addition of glycine to the growth medium relieved the effect of TDZ on the muropeptide profile. Furthermore, exogenous glycine offered a modest protective effect against TDZ-induced Î²-lactam sensitivity. We propose that TDZ exposure leads to a shortage of intracellular amino acids, including glycine, which is required for the production of normal peptidoglycan precursors with pentaglycine branches, the correct substrate of S. aureus penicillin-binding proteins. Collectively, this work demonstrates that TDZ has a major impact on the cell wall biosynthesis pathway in S. aureus and provides new insights into how MRSA may be sensitized towards Î²-lactam antibiotics. Staphylococcus aureus USA300 was grown to early exponential phase and treated with TDZ (16 Âµg/ml) alone or in combination with DCX (0.125 Âµg/ml) for 30 min. Changes in global gene expression were analyzed using the untreated culture as control. Hybridizations were performed in triplicate using RNA isolated from independent cultures.

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Whole-transcriptome analysis of Staphylococcus aureus under laboratory and infection-mimicking conditions

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