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Staphylococcus aureus walKR mutants (TPS3130 and TPS3190) vs. parent strains (JKD6009 and JKD6004)

ABSTRACT: WalKR is an essential two component regulatory system in S. aureus, thought to control cell wall metabolism. Using genome sequencing of 5 paired clinical isolates of vancomycin-susceptible and vancomycin-intermediate S. aureus we found frequent, but unique, mutations in this locus. To investigate the contribution of these mutations to vancomycin resistance allelic replacement WalK (G223D) and WalR (K208R) mutants were generated and compared to the parent strains. Mutations in walk and walR led to increased vancomycin resistance, reduced biofilms formation and attenuation of virulence, demonstrating that minor genetic changes in this locus can lead to significant changes in bacterial resistance and virulence. Microarray transcriptional comparisons were performed to investigate the regulatory effects of the WalK (G223D) and WalR (K208R) mutations, and demonstrated that while changes in genes affecting cell wall metabolism were detected, more dramatic changes were found in regulation of cellular metabolism. Transcriptional profiling of laboratory derived S. aureus walKR mutants compared to the parent isolates. TPS3130 has a single point mutation in walK, and TPS3190 has a single point mutation in walR. Two condition experiment TPS3130 vs JKD6009 and TPS3190 vs JKD6004. 3 biological replicates per isolate pair, one replicate per slide.

ORGANISM(S): Staphylococcus aureus

SUBMITTER: Benjamin Howden

PROVIDER: E-GEOD-29157 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Staphylococcus aureus walKR mutants (TPS3130 and TPS3190) vs. parent strains (JKD6009 and JKD6004)

Project description:WalKR is an essential two component regulatory system in S. aureus, thought to control cell wall metabolism. Using genome sequencing of 5 paired clinical isolates of vancomycin-susceptible and vancomycin-intermediate S. aureus we found frequent, but unique, mutations in this locus. To investigate the contribution of these mutations to vancomycin resistance allelic replacement WalK (G223D) and WalR (K208R) mutants were generated and compared to the parent strains. Mutations in walk and walR led to increased vancomycin resistance, reduced biofilms formation and attenuation of virulence, demonstrating that minor genetic changes in this locus can lead to significant changes in bacterial resistance and virulence. Microarray transcriptional comparisons were performed to investigate the regulatory effects of the WalK (G223D) and WalR (K208R) mutations, and demonstrated that while changes in genes affecting cell wall metabolism were detected, more dramatic changes were found in regulation of cellular metabolism.

2012-06-01 | GSE29157 | GEO

Switching on antibiotic resistance in Staphylococcus aureus M-bM-^@M-^S Contribution of WalK and VraS histidine kinases in the development of vancomycin and daptomycin resistance

Project description:Staphylococcus aureus is a notorious bacterial pathogen that causes a broad range of human diseases, and isolates that are resistant to several antibiotic classes including last resort antibiotics like vancomycin and daptomycin complicate the situation. We characterized S. aureus VC40, a strain that shows full resistance to vancomycin (MIC of 64 M-BM-5g/ml) and daptomycin (MIC of 4 M-BM-5g/ml) as well as a decreased susceptibility to further cell wall active agents. Genome sequencing revealed mutations in genes encoding the histidine kinases WalK and VraS that control cell envelope related processes and gene expression profiling indicated the induction of the respective regulons in strain VC40. Reconstitution of the mutations in walK or vraS into the susceptible S. aureus NCTC 8325 background resulted in a considerably increased resistance to vancomycin and daptomycin with MICs surpassing the clinical breakpoints for these antibiotics, thereby generating vancomycin-intermediate S. aureus (VISA) strains. As observed for S. aureus VC40, the walKwalk and vraS mutations also led to an increased expression of the respective regulons in the NCTC 8325 background. Phenotypic studies showed that S. aureus VC40 as well as the walKwalk and vraS mutants of strain NCTC 8325 were characterized by a significantly thickened cell wall, a decreased growth rate, a reduced autolytic activity and an increased resistance to lysostaphin-induced lysis. These results demonstrate that the WalK and VraS histidine kinases act as major switches which allow S. aureus to rapidly develop vancomycin resistance up to the VISA level via mutation of one single gene locus and concomitantly contribute to cross-resistance to other antibiotics including the last resort antibiotic daptomycin. Microarray was used to evaluate alteration in the transcriptome of mutS mutant and compared to the parental strain VC40

2014-08-18 | E-GEOD-46887 | biostudies-arrayexpress

Switching on antibiotic resistance in Staphylococcus aureus – Contribution of WalK and VraS histidine kinases in the development of vancomycin and daptomycin resistance

Project description:Staphylococcus aureus is a notorious bacterial pathogen that causes a broad range of human diseases, and isolates that are resistant to several antibiotic classes including last resort antibiotics like vancomycin and daptomycin complicate the situation. We characterized S. aureus VC40, a strain that shows full resistance to vancomycin (MIC of 64 µg/ml) and daptomycin (MIC of 4 µg/ml) as well as a decreased susceptibility to further cell wall active agents. Genome sequencing revealed mutations in genes encoding the histidine kinases WalK and VraS that control cell envelope related processes and gene expression profiling indicated the induction of the respective regulons in strain VC40. Reconstitution of the mutations in walK or vraS into the susceptible S. aureus NCTC 8325 background resulted in a considerably increased resistance to vancomycin and daptomycin with MICs surpassing the clinical breakpoints for these antibiotics, thereby generating vancomycin-intermediate S. aureus (VISA) strains. As observed for S. aureus VC40, the walKwalk and vraS mutations also led to an increased expression of the respective regulons in the NCTC 8325 background. Phenotypic studies showed that S. aureus VC40 as well as the walKwalk and vraS mutants of strain NCTC 8325 were characterized by a significantly thickened cell wall, a decreased growth rate, a reduced autolytic activity and an increased resistance to lysostaphin-induced lysis. These results demonstrate that the WalK and VraS histidine kinases act as major switches which allow S. aureus to rapidly develop vancomycin resistance up to the VISA level via mutation of one single gene locus and concomitantly contribute to cross-resistance to other antibiotics including the last resort antibiotic daptomycin.

2014-08-18 | GSE46887 | GEO

Cervimycin resistant Staphylococcus aureus strains display a vancomycin intermediate resistant phenotype

Project description:Resistance to antibiotics is an emerging problem and necessitates novel antibacterial therapies. Cervimycins A‒D are natural products of Streptomyces tendae HKI 0179 with promising activity against multidrug resistant staphylococci and vancomycin resistant enterococci. We studied the mode of action of cervimycin C and D by selection of cervimycin resistant (CmR) Staphylococcus aureus strains. Genome sequencing of CmR mutants revealed amino acid exchanges in the essential histidine kinase WalK, the Clp protease proteolytic subunit ClpP or the Clp ATPase ClpC, and the heat shock protein DnaK. Interestingly, all characterized cervimycin resistant mutants harbored a combination of mutations in walK and clpP or clpC. Mutations in the Clp system abolished ClpP or ClpC activity, and the deletion of clpP rendered S. aureus but not B. subtilis cervimycin resistant. The essential gene walK was the second mutational hotspot in the cervimycin resistant S. aureus mutants, which decreased WalK activity in vitro and generated a vancomycin intermediately resistant phenotype, with a thickened cell wall, a slower growth rate, and reduced cell lysis. Transcriptomic and proteomic analysis revealed massive alterations in the CmR strains , with major alterations in the heat shock regulon, the metal ion homeostasis and the carbohydrate metabolism. Taken together, compensatory mutations in cervimycin resistant mutants induced a VISA phenotype in S. aureus, suggesting cell wall metabolism or the ClpCP proteolytic system as primary target of the polyketide antibiotic

2022-09-08 | GSE206309 | GEO

Proteome analysis of Staphylococcus aureus strains

Project description:Cervimycins A‒D are natural products of Streptomyces tendae HKI 0179 with promising activity against multidrug resistant staphylococci and vancomycin resistant enterococci. To initiate mode of action studies, we selected cervimycin C and D resistant (CmR) Staphylococcus aureus strains. Genome sequencing of CmR mutants revealed amino acid exchanges in the essential histidine kinase WalK, the Clp protease proteolytic subunit ClpP or the Clp ATPase ClpC, and the heat shock protein DnaK. Proteomic analysis revealed massive alterations in CmR-02 (amino acid exchanges: ClpP-I29F, DnaK-A112P, WalK-A243V) compared to the parent strain S. aureus SG511 Berlin, with major modifications in the heat shock regulon, the metal ion homeostasis and the carbohydrate metabolism. These effects were alleviated in the antibiotic susceptible suppressor mutant 02REV (amino acid exchanges: ClpP-I29F/M31I, WalK-A243V/S191L).

2022-09-22 | PXD034970 | Pride

Gene expression analysis of Vancomycin resistance in Stapyloccoccus aureus strains: 2275, 2279, 2276, 2277, 2278, and 2283.

Project description:Understanding novel mechanism bacteria ustilize in the clinics to become resistant to antibiotics is critical. The study aims to identify genes associated with Vancomycin resistance. Clinical isolates from a single patient with increasing resistance to vancomycin were grown in the presence and absence of vancomycin.Staphylococcus aureus strain 2275 is the reference for this series. S. aureus isolates from a single patient were grown in the presence and absence of vancomycin over a 2 hour time course. RNA samples were extracted at 30, 60 90 and 120 minutes post exposure to antibiotic. Samples were hybridized on aminosilane coated slides with 70-mer oligos comparing mock treated and treated cells to the first strain isolated in the lineage. Differnetial gene expression patterns were determined.

2011-04-08 | E-GEOD-26353 | biostudies-arrayexpress

Gene expression analysis of Vancomycin resistance in Stapyloccoccus aureus strains: 2275, 2279, 2276, 2277, 2278, and 2283.

2011-04-08 | GSE26353 | GEO

Staphylococcus aureus small colony variant (JKD6229) vs. parent strain (JKD6210)

Project description:Transcriptional profiling of the small colony variant (SCV) S. aureus isolate (JKD6229) compared to the parent isolate with a normal phenotype (JKD6210). Both isolates were from a patient with persistent S. aureus infection, and the SCV strain arose during failed antibiotic therapy. Two condition experiment JKD6229 vs JKD6210. 4 biological replicates, one replicate per slide.

2010-08-13 | E-GEOD-20957 | biostudies-arrayexpress

Metabolome of three Vancomycin-intermediate Staphylococcus aureus (VISA) mutants compared with the parent strain MM66

Project description:Vancomycin-intermediate Staphylococcus aureus (VISA) evolve in a strain-specific manner and acquire mutations that lead to alterations in cell wall metabolism that reduce susceptibility to vancomycin. We had earlier isolated several VISA mutant strains of the clinical hVISA strain MM66. This study is aimed at analyzing the metabolome of these mutants in comparison to the parent strain.

2016-01-12 | ST000309 | MetabolomicsWorkbench

Genomic and Long-Term Transcriptomic Imprints Related to the Daptomycin Mechanism of Action Occurring in Daptomycin- and Methicillin-Resistant Staphylococcus aureus Under Daptomycin Exposure

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