scholarly journals cwrA, a gene that specifically responds to cell wall damage in Staphylococcus aureus

Microbiology ◽  
2010 ◽  
Vol 156 (5) ◽  
pp. 1372-1383 ◽  
Author(s):  
Carl J. Balibar ◽  
Xiaoyu Shen ◽  
Dorothy McGuire ◽  
Donghui Yu ◽  
David McKenney ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Transcriptional Profiling ◽  
Wall Stress ◽  
Penicillin G ◽  
Cell Wall Stress ◽  
Cell Wall Biogenesis ◽  
Carbonyl Cyanide ◽  
A Cell ◽  
Cell Wall Inhibition

Transcriptional profiling data accumulated in recent years for the clinically relevant pathogen Staphylococcus aureus have established a cell wall stress stimulon, which comprises a coordinately regulated set of genes that are upregulated in response to blockage of cell wall biogenesis. In particular, the expression of cwrA (SA2343, N315 notation), which encodes a putative 63 amino acid polypeptide of unknown biological function, increases over 100-fold in response to cell wall inhibition. Herein, we seek to understand the biological role that this gene plays in S. aureus. cwrA was found to be robustly induced by all cell wall-targeting antibiotics tested – vancomycin, oxacillin, penicillin G, phosphomycin, imipenem, hymeglusin and bacitracin – but not by antibiotics with other mechanisms of action, including ciprofloxacin, erythromycin, chloramphenicol, triclosan, rifampicin, novobiocin and carbonyl cyanide 3-chlorophenylhydrazone. Although a ΔcwrA S. aureus strain had no appreciable shift in MICs for cell wall-targeting antibiotics, the knockout was shown to have reduced cell wall integrity in a variety of other assays. Additionally, the gene was shown to be important for virulence in a mouse sepsis model of infection.

Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon

Microbiology ◽  
2003 ◽  
Vol 149 (10) ◽  
pp. 2719-2732 ◽  
Author(s):  
S. Utaida ◽  
P. M. Dunman ◽  
D. Macapagal ◽  
E. Murphy ◽  
S. J. Projan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Stress Responses ◽  
Transcriptional Profiling ◽  
Wall Stress ◽  
Antibacterial Activities ◽  
Transcriptional Signature ◽  
Genome Wide ◽  
Custom Made ◽  
A Cell

The molecular events following inhibition of bacterial peptidoglycan synthesis have not been studied extensively. Previous proteomic studies have revealed that certain proteins are produced in increased amounts upon challenge of Staphylococcus aureus with cell-wall-active antibiotics. In an effort to further those studies, the genes upregulated in their expression in response to cell-wall-active antibiotics have been identified by genome-wide transcriptional profiling using custom-made Affymetrix S. aureus GeneChipsTM. A large number of genes, including ones encoding proteins involved in cell-wall metabolism (including pbpB, murZ, fmt and vraS) and stress responses (including msrA, htrA, psrA and hslO), were upregulated by oxacillin, d-cycloserine or bacitracin. This response may represent the transcriptional signature of a cell-wall stimulon induced in response to cell-wall-active agents. The findings imply that treatment with cell-wall-active antibiotics results in damage to proteins including oxidative damage. Additional genes in a variety of functional categories were upregulated uniquely by each of the three cell-wall-active antibiotics studied. These changes in gene expression can be viewed as an attempt by the organism to defend itself against the antibacterial activities of the agents.

scholarly journals Transcriptional Profiling Reveals that Daptomycin Induces the Staphylococcus aureus Cell Wall Stress Stimulon and Genes Responsive to Membrane Depolarization

2007 ◽  
Vol 52 (3) ◽  
pp. 980-990 ◽  
Author(s):  
Arunachalam Muthaiyan ◽  
Jared A. Silverman ◽  
Radheshyam K. Jayaswal ◽  
Brian J. Wilkinson
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Mode Of Action ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Transcriptional Profiling ◽  
Wall Stress ◽  
Membrane Depolarization ◽  
Transcriptional Responses ◽  
Cell Wall Stress

ABSTRACT Daptomycin is a lipopeptide antibiotic that has recently been approved for treatment of gram-positive bacterial infections. The mode of action of daptomycin is not yet entirely clear. To further understand the mechanism transcriptomic analysis of changes in gene expression in daptomycin-treated Staphylococcus aureus was carried out. The expression profile indicated that cell wall stress stimulon member genes (B. J. Wilkinson, A. Muthaiyan, and R. K. Jayaswal, Curr. Med. Chem. Anti-Infect. Agents 4:259-276, 2005) were significantly induced by daptomycin and by the cell wall-active antibiotics vancomycin and oxacillin. Comparison of the daptomycin response of a two-component cell wall stress stimulon regulator VraSR mutant, S. aureus KVR, to its parent N315 showed diminished expression of the cell wall stress stimulon in the mutant. Daptomycin has been proposed to cause membrane depolarization, and the transcriptional responses to carbonyl cyanide m-chlorophenylhydrazone (CCCP) and nisin were determined. Transcriptional profiles of the responses to these antimicrobial agents showed significantly different patterns compared to those of the cell wall-active antibiotics, including little or no induction of the cell wall stress stimulon. However, there were a significant number of genes induced by both CCCP and daptomycin that were not induced by oxacillin or vancomycin, so the daptomycin transcriptome probably reflected a membrane depolarizing activity of this antimicrobial also. The results indicate that inhibition of peptidoglycan biosynthesis, either directly or indirectly, and membrane depolarization are parts of the mode of action of daptomycin.

scholarly journals Mutations inmmpLand in the Cell Wall Stress Stimulon Contribute to Resistance to Oxadiazole Antibiotics in Methicillin-Resistant Staphylococcus aureus

2014 ◽  
Vol 58 (10) ◽  
pp. 5841-5847 ◽  
Author(s):  
Qiaobin Xiao ◽  
Sergei Vakulenko ◽  
Mayland Chang ◽  
Shahriar Mobashery
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Stress ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Wall Stress ◽  
A Cell ◽  
Putative Member

ABSTRACTStaphylococcus aureusis a leading cause of hospital- and community-acquired infections, which exhibit broad resistance to various antibiotics. We recently disclosed the discovery of the oxadiazole class of antibiotics, which hasin vitroandin vivoactivities against methicillin-resistantS. aureus(MRSA). We report herein that MmpL, a putative member of the resistance, nodulation, and cell division (RND) family of proteins, contributes to oxadiazole resistance in theS. aureusstrain COL. Through serial passages, we generated twoS. aureusCOL variants that showed diminished susceptibilities to an oxadiazole antibiotic. The MICs for the oxadiazole against one strain (designatedS. aureusCOLI) increased reproducibly 2-fold (to 4 μg/ml), while against the other strain (S. aureusCOLR), they increased >4-fold (to >8 μg/ml, the limit of solubility). The COLRstrain was derived from the COLIstrain. Whole-genome sequencing revealed 31 mutations inS. aureusCOLR, of which 29 were shared with COLI. Consistent with our previous finding that oxadiazole antibiotics inhibit cell wall biosynthesis, we found 13 mutations that occurred either in structural genes or in promoters of the genes of the cell wall stress stimulon. Two unique mutations inS. aureusCOLRwere substitutions in two genes that encode the putative thioredoxin (SACOL1794) and MmpL (SACOL2566). A role formmpLin resistance to oxadiazoles was discerned from gene deletion and complementation experiments. To our knowledge, this is the first report that a cell wall-acting antibiotic selects for mutations in the cell wall stress stimulon and the first to implicate MmpL in resistance to antibiotics inS. aureus.

scholarly journals Epigallocatechin Gallate Induces Upregulation of the Two-Component VraSR System by Evoking a Cell Wall Stress Response in Staphylococcus aureus

2012 ◽  
Vol 78 (22) ◽  
pp. 7954-7959 ◽  
Author(s):  
Oren Levinger ◽  
Tamar Bikels-Goshen ◽  
Elad Landau ◽  
Merav Fichman ◽  
Roni Shapira
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Epigallocatechin Gallate ◽  
Wall Stress ◽  
Null Mutant ◽  
Wild Type ◽  
Content Type ◽  
Cell Wall Stress ◽  
Two Component ◽  
A Cell

ABSTRACTWe previously found that a short exposure ofStaphylococcus aureusto subinhibitory (SI) doses of epigallocatechin gallate (EGCG) results in increased cell wall thickness, adaptation, and enhanced tolerance to cell-wall-targeted antibiotics. In this study, the response to EGCG ofsigBandvraSRtranscription factor mutants was characterized. We show that in contrast to the results observed for wild-type (WT) strains, anS. aureus315vraSRnull mutant exposed to SI doses of EGCG did not exhibit increased tolerance to EGCG and oxacillin. A diminished increase in tolerance to ampicillin (from 16-fold to 4-fold) and no change in the magnitude of resistance to vancomycin were observed. Preexposure to EGCG enhanced the tolerance of wild-type andsigBnull mutant cells to lysostaphin, but this enhancement was much weaker in thevraSRnull mutant. Marked upregulation (about 60-fold) ofvraRand upregulation of the peptidoglycan biosynthesis-associated genesmurA,murF, andpbp2(2-, 5-, and 6-fold, respectively) in response to SI doses of EGCG were determined by quantitative reverse transcription-PCR (qRT-PCR). EGCG also induced the promoter ofsas016(encoding a cell wall stress protein of unknown function which is not induced invraSRnull mutants) in a concentration-dependent manner, showing kinetics comparable to those of cell-wall-targeting antibiotics. Taken together, our results suggest that the two-component VraSR system is involved in modulating the cell response to SI doses of EGCG.

scholarly journals Small Alarmone Synthetases RelP and RelQ of Staphylococcus aureus Are Involved in Biofilm Formation and Maintenance Under Cell Wall Stress Conditions

2020 ◽  
Vol 11 ◽  
Author(s):  
Andrea Salzer ◽  
Daniela Keinhörster ◽  
Christina Kästle ◽  
Benjamin Kästle ◽  
Christiane Wolz
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Biofilm Formation ◽  
Wall Stress ◽  
Stress Conditions ◽  
Cell Wall Stress

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

2005 ◽  
Vol 4 (3) ◽  
pp. 259-276 ◽  
Author(s):  
Brian Wilkinson ◽  
Arunachalam Muthaiyan ◽  
Radheshyam Jayaswal
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Stress ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Cell Wall Stress

scholarly journals The Posttranslocational Chaperone Lipoprotein PrsA Is Involved in both Glycopeptide and Oxacillin Resistance in Staphylococcus aureus

2012 ◽  
Vol 56 (7) ◽  
pp. 3629-3640 ◽  
Author(s):  
Ambre Jousselin ◽  
Adriana Renzoni ◽  
Diego O. Andrey ◽  
Antoinette Monod ◽  
Daniel P. Lew ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Stress ◽  
Growth Conditions ◽  
Transcriptional Analysis ◽  
Pharmacological Intervention ◽  
Content Type ◽  
Cell Wall Stress ◽  
Oxacillin Resistance ◽  
Mrsa Strains

ABSTRACTUnderstanding in detail the factors which permitStaphylococcus aureusto counteract cell wall-active antibiotics is a prerequisite to elaborating effective strategies to prolong the usefulness of these drugs and define new targets for pharmacological intervention. Methicillin-resistantS. aureus(MRSA) strains are major pathogens of hospital-acquired and community-acquired infections and are most often treated with glycopeptides (vancomycin and teicoplanin) because of their resistance to most penicillins and a limited arsenal of clinically proven alternatives. In this study, we examined PrsA, a lipid-anchored protein of the parvulin PPIase family (peptidyl-prolylcis/transisomerase) found ubiquitously in all Gram-positive species, in which it assists posttranslocational folding at the outer surface of the cytoplasmic membrane. We show by both genetic and biochemical assays thatprsAis directly regulated by the VraRS two-component sentinel system of cell wall stress. Disruption ofprsAis tolerated byS. aureus, and its loss results in no detectable overt macroscopic changes in cell wall architecture or growth rate under nonstressed growth conditions. Disruption ofprsAleads, however, to notable alterations in the sensitivity to glycopeptides and dramatically decreases the resistance of COL (MRSA) to oxacillin. Quantitative transcriptional analysis reveals thatprsAandvraRare coordinately upregulated in a panel of stable laboratory and clinical glycopeptide-intermediateS. aureus(GISA) strains compared to their susceptible parents. Collectively, our results point to a role forprsAas a facultative facilitator of protein secretion or extracellular folding and provide a framework for understanding whyprsAis a key element of the VraRS-mediated cell wall stress response.

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