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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A mutation in PP2C Phosphatase Gene in a Staphylococcus aureus USA300 Clinical Isolate with Reduced Susceptibility to Vancomycin and Daptomycin

ABSTRACT: Investigation of baseline transcription activity of two different clinical isolates of Staphylococcus aureus with two different susceptibility levels to the antibiotics Vancomycin and Daptomycin. Two different strains of Staphylococcus aureus, one that is fully Vancomycin and Daptomycin Sensitive and one with decreased Vancomycin and Daptomycin Sensitivity - grown to mid-log phase in rich broth.

ORGANISM(S): Staphylococcus aureus

SUBMITTER: Tim Read

PROVIDER: E-GEOD-39868 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A mutation in the PP2C phosphatase gene in a Staphylococcus aureus USA300 clinical isolate with reduced susceptibility to vancomycin and daptomycin.

Passalacqua Karla D KD Satola Sarah W SW Crispell Emily K EK Read Timothy D TD

Antimicrobial agents and chemotherapy 20120730 10

Methicillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (MIC of 4 to 8 μg/ml) are referred to as vancomycin-intermediate S. aureus (VISA). In this study, we characterized two isogenic USA300 S. aureus isolates collected sequentially from a single patient with endocarditis where the S. aureus isolate changed from being susceptible to vancomycin (VSSA) (1 μg/ml) to VISA (8 μg/ml). In addition, the VISA isolate lost beta-lactamase activity and showed inc ...[more]

PMID: 22850507

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A mutation in PP2C Phosphatase Gene in a Staphylococcus aureus USA300 Clinical Isolate with Reduced Susceptibility to Vancomycin and Daptomycin

Project description:Investigation of baseline transcription activity of two different clinical isolates of Staphylococcus aureus with two different susceptibility levels to the antibiotics Vancomycin and Daptomycin.

2012-08-03 | GSE39868 | GEO

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

Project description:Daptomycin (DAP) is the last-resort treatment for heterogeneous Vancomycin-Intermediate-Staphylococcus aureus (hVISA) and Vancomycin-Intermediate-S.aureus (VISA), and DAP-resistance onset which is also linked to reduced vancomycin susceptibility, is an increasing public health problem. To have more insight into the mechanisms of daptomycin resistance, the comparative transcriptomes of two DAP-R (1C-3B) clinical isogenic isolates vs their DAP-S (1A-3A) counterparts were investigated by Illumina RNA-seq, the Rockhopper tool, computational filtering analyses and bioinformatic tools.

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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.

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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

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Transcriptional Profiling of Daptomycin Induced Staphylococcus aureus

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Project description:The human pathogen Staphylococcus aureus encodes a specialised type VII secretion system (T7SS), which plays an important role in bacterial virulence during infection. However, the functions the T7SS during infection and in bacterial physiology remain unclear. Here we demonstrate that S. aureus strains lacking the transporter EssC as well as the T7SS effectors, EsxC and EsxA were highly sensitive to the important last resort drug, daptomycin as well as other membrane-targeting antibiotics, including gramicidin and bithionol. To understand how T7SS mediates increased antibiotic sensitivity, we investigated the impact of T7SS on the staphylococcal cell envelope. Interestingly, T7SS mutants displayed decreased membrane fluidity with altered localisation of cell membrane proteins such as flotillin under normal growth conditions. LC/MS analysis showed different protein profiles in the mutant membrane preparations compared to the WT, suggesting that T7SS impacts membrane homeostasis. Scanning electron microscopy analysis demonstrated distinct cell surface morphologies for the T7SS mutants, with altered cell wall synthesis as well cell surface charge. In line with the increased negative surface charge, daptomycin binding was enhanced in the mutants, which demonstrated increased membrane permeability when treated with the drug. T7SS mutants were more sensitive to daptomycin during intracellular infection, and furthermore, in a murine skin infection model, esxC mutants survived less than the WT when treated with daptomycin. Thus, our data show that the T7SS impacts sensitivity of S. aureus to membrane-acting drugs such as daptomycin through modulation of cell membrane integrity, indicating its potential as a drug target

2024-04-19 | PXD047096 | Pride

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Project description:The glycopeptide antibiotic vancomycin (VCM) represents one of the last lines of defense against methicillin-resistant Staphylococcus aureus infections. However, vancomycin is nephrotoxic, but the mechanism of toxicity is still unclear. The goal of this study was twofold: (1) gain insights into the molecular mechanisms of vancomycin nephrotoxicity at the genomic level and (2) evaluate potential biomarkers (gene expression profiles) of vancomycin-induced kidney injury Keywords: Dose response

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Project description:Novel anti-infective agents targeting Staphylococcus aureus and capable of increasing S. aureus susceptibility towards antibiotics are needed. One alternative approach is targeting the bacterial quorum sensing (QS) system. QS is a process by which bacteria produce and detect signal molecules and thereby coordinate their behaviour, virulence and biofilm formation in a cell-density-dependent manner. Hamamelitannin (HAM) was previously suggested to target the S. aureus QS system, thereby increasing the susceptibility of S. aureus biofilms towards vancomycin. However, mechanistic insights are still lacking. For this reason, we evaluated the effect of Hamamelitannin, vancomycin and combination treatment of Hamamelitannin and vancomycin on gene expression in S. aureus Mu50 biofilms.

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