Oxacillin-induced inhibition of protein and RNA synthesis in a tolerant Staphylococcus aureus isolate

Jablonski, Peter E.; Mychajlonka, Myron

doi:10.1128/jb.170.4.1831-1836.1988

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…some genes are being selectively expressed. In an earlier study Jablonski and Mychajlonka [21] showed using one‐dimensional gel electrophoresis, alterations in S. aureus protein synthesis in response to oxacillin. The set of proteins that was observed to be produced in response to the various cell wall‐active antibiotics studied may represent a proteomic signature.…”

Section: Resultsmentioning

confidence: 99%

Cell wall-active antibiotic induced proteins of Staphylococcus aureus identified using a proteomic approach1

Singh¹,

Jayaswal²,

Wilkinson³

2001

FEMS Microbiology Letters

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Proteins produced in elevated amounts in response to oxacillin challenge of Staphylococcus aureus strain RN450, were studied by comparing Coomassie blue stained two-dimensional gels of cellular proteins. At least nine proteins were produced in elevated amounts following exposure to growth inhibitory concentrations of oxacillin. N-terminal sequences were obtained for five of the proteins and the databases were searched to tentatively identify them. The proteins were identified as homologs of (i) methionine sulfoxide reductase (MsrA); (ii) a signal transduction protein (TRAP) involved in regulating RNAIII production encoded by the agr locus; (iii) transcription elongation factor GreA; (iv) the heat shock protein GroES; and (v) the enzyme IIA component of the phosphoenolpyruvate:sugar phosphotransferase system. A similar induction response was observed with the other cell wall-active antibiotics, but not with antibiotics that affect other cellular targets. Increased transcription of the msrA and groEL genes in response to cell wall-active antibiotics was also demonstrated. Although net protein synthesis is inhibited subsequent to inhibition of peptidoglycan biosynthesis by cell wall-active antibiotics, some proteins are induced in S. aureus, presumably in an attempt by the cell to counter the inhibitory effects of these agents.

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Section: Resultsmentioning

confidence: 99%

Cell wall-active antibiotic induced proteins of Staphylococcus aureus identified using a proteomic approach1

Singh¹,

Jayaswal²,

Wilkinson³

2001

FEMS Microbiology Letters

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“…Inhibition of these targets not only causes interference with bacterial growth but also invokes in the cells rapid changes in the pattern of transcription of a large number of genes (11,22,35), suggesting the existence of complex regulatory loops which link a wide variety of steps in metabolism to some steps in cell wall biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

Extensive and Genome-Wide Changes in the Transcription Profile ofStaphylococcus aureusInduced by Modulating the Transcription of the Cell Wall Synthesis GenemurF

et al. 2007

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A murF conditional mutant was used to evaluate the effect of suboptimal transcription of this gene on the transcriptome of the methicillin-resistant Staphylococcus aureus strain COL. The mutant was grown in the presence of optimal and suboptimal concentrations of the inducer, and the relative levels of transcription of genes were evaluated genome wide with an Affymetrix DNA microarray that included all open reading frames (ORFs) as well as intergenic sequences derived from four sequenced S. aureus strains. Using a sensitivity threshold value of 1.5, suboptimal expression of murF altered the transcription of a surprisingly large number of genes, i.e., 668 out of the 2,740 ORFs (close to one-fourth of all ORFs), of the genome of S. aureus strain COL. The genes with altered transcription were distributed evenly around the S. aureus chromosome, and groups of genes involved with distinct metabolic functions responded in unique and operon-specific manners to modulation in murF transcription. For instance, all genes belonging to the isd operon and all but 2 of the 35 genes of prophage L54a were down-regulated, whereas all but one of the 21 members of the vraSR regulon and most of the 79 virulence-related genes (those for fibronectin binding proteins A and B, clumping factor A, gamma hemolysin, enterotoxin B, etc.) were up-regulated in cells with suboptimal expression of murF. Most importantly, the majority of these altered gene expression profiles were reversible by resupplying the optimal concentration of IPTG (isopropyl-␤-D-thiogalactopyranoside) to the culture. The observations suggest the coordinate regulation of a large sector of the S. aureus transcriptome in response to a disturbance in cell wall synthesis.Transcriptomic approaches are powerful tools for the identification of groups of genes with similar expression patterns and for the establishment of putative regulatory relations between them. Using microarray technology, recent reports have described extensive changes in gene expression profiles when Staphylococcus aureus was challenged by different cell wall inhibitors such as oxacillin, bacitracin, D-cycloserine, and vancomycin (12, 19, 20, 34). The group of genes whose transcription was altered during treatment with antibiotics that target different steps in cell wall synthesis was proposed to represent members of a cell wall stimulon responding to a specific form of stress in a coordinate manner.The large number and diversity of genes that respond to cell wall inhibitors by altered transcription suggest that many functions of the bacterial cell are connected through regulatory loops to one or more steps in cell wall synthesis which may also serve as control points of metabolism. Such a control should also be operational in the absence of antibiotic treatment, and we searched for a system in which the existence of such a regulatory system could be experimentally demonstrated.The method of choice became available with the isolation of an S. aureus murF conditional mutant in which the rate of transcription o...

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“…It is interesting to note that Jablonski and Mychajlonka [28] observed that oxacillin challenge of a tolerant S. aureus caused an initial stimulation of RNA synthesis. The genes induced belonged to functional categories that included amino acid transport and metabolism, carbohydrate transport and metabolism, cell-envelope biogenesis, DNA replication, recombination and repair, post-translational modification, protein turnover and chaperones, signal transduction mechanisms, and transcription.…”

Section: The S Aureus Cell Wall Stress Stimulonmentioning

confidence: 98%

“…A regulon is a network of operons controlled by a common regulatory protein. During this time the response of bacteria to cell wall-active antibiotics came to be viewed as a stress response system [28][29][30].…”

Section: The S Aureus Cell Wall Stress Stimulonmentioning

confidence: 99%

The Cell Wall Stress Stimulon of Staphylococcus aureus and Other Gram- Positive Bacteria

Wilkinson¹,

Muthaiyan²,

Jayaswal³

2005

CMCAIA

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By the early nineteen seventies the mechanism of inhibition of peptidoglycan biosynthesis by various cell wallactive antibiotics was well established, and the Gram-positive bacterium Staphylococcus aureus had often been used in the studies. From the early days of penicillin it was known that cell wall-active antibiotics are typically bactericidal causing cell death and lysis, a phenomenon that has recently been described as programmed cell death. Uncovering the details of the molecular and cellular events occurring subsequent to inhibition of peptidoglycan biosynthesis, a legitimate aspect of knowledge of the mode of action of these agents, has had to await the advent of the omics era-genomics, proteomics and transcriptomics-over the past several years. Genome-wide transcriptional profiling using DNA microarrays of the response of S. aureus to challenge by cell wall active antibiotics has revealed a cell wall stress stimulon of genes upregulated in their expression by these agents. Several of the genes encode proteins involved in cell wall metabolism and their induction can be regarded as a response of the organism to preserve and repair the compromised cell wall. Expression of a significant number of cell wall stress stimulon member genes is controlled by a two-component regulatory system. Cell wall stress stimulons regulated by two-component systems have also been described in Bacillus subtilis and Listeria monocytogenes, and are probably common to all Gram-positive bacteria. Unfortunately S. aureus has not remained susceptible to cell wall-active antibiotics and methicillin-resistant strains are common, and vancomycinintermediate and-resistant strains have arisen. Interestingly, some member genes of the cell wall stress stimulon have been previously encountered in the context of methicillin-resistance or vancomycin-intermediate resistance. There is a threat of pan-resistant S. aureus strains and new antimicrobial agents are needed. Cell wall biosynthesis remains a viable target for new drugs, and recognition of the transcriptomic signature of the cell wall stress stimulon can be used to indicate a cell wall mode of action. Individual cell wall stress member genes may form the basis of a screen for cell wall-active agents. Finally, agents targeting cell wall stress stimulon member gene expression or proteins might enhance the activity of cell wall-active agents that induce the cell wall stress stimulon.

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Oxacillin-induced inhibition of protein and RNA synthesis in a tolerant Staphylococcus aureus isolate

Cited by 8 publications

References 14 publications

Cell wall-active antibiotic induced proteins of Staphylococcus aureus identified using a proteomic approach1

Cell wall-active antibiotic induced proteins of Staphylococcus aureus identified using a proteomic approach1

Extensive and Genome-Wide Changes in the Transcription Profile ofStaphylococcus aureusInduced by Modulating the Transcription of the Cell Wall Synthesis GenemurF

The Cell Wall Stress Stimulon of Staphylococcus aureus and Other Gram- Positive Bacteria

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