Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1150419 | ENA |
REPOSITORIES: ENA
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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
Project description:Novel molecules were tested against S. aureus strains and seen to be effective. We explored the possibilities of resistance arising. We saw that after exposure to sub-MIC concentrations of novel PYO antibiotics S. aureus became slightly resistant to PYO compounds. Resistant mutants were sequenced and data submitted to EVA.
2025-02-28 | PRJEB86156 | EVA
Project description:Staphylococcus aureus NRS384 rifampicin resistant mutants
| PRJNA399605 | ENA
Project description:Staphylococcus aureus is a human commensal bacterium and opportunistic pathogen. Chronicity of S. aureus infection has been linked to bacterial survival within host cells including macrophages. Bacteria recovered from the intracellular milieu often form small colony variants (SCV) which are growing slowly, show reduced virulence factor production and are more resistant to antibiotics. Branched chain amino acids (BCAA) are an important class of nutrients for S. aureus. We therefore tested if components of BCAA biosynthesis or transport would alter the outcome of macrophage infection. We found that S. aureus mutants in the BCAA transporter BrnQ1 survived experimental infection of primary human macrophages for the complete duration of the 28 day experiments. Since phenotypic differences between brnQ1 mutants and wild-type bacteria occurred around 10 h p.i., we performed dual RNA-seq by which we determined the transcriptomes of both, pathogen and macrophage host, simultaneously. Our data indicate that at that time transcriptomic changes exclusively are governed by the internalized pathogen. The differential analysis of S. aureus WT and its isogenic brnQ1 mutant surprisingly demonstrated a dysregulation of iron-dependently regulated genes.
2023-06-28 | GSE235929 | GEO
Project description:The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in multi-drug resistant bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system, and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. Here we show that in vitro serial passage of a clinical USA300 methicillin-resistant Staphylococcus aureus strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP-resistance. AMP-resistant S. aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defense peptides. These findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.
2016-09-26 | PXD004036 | Pride
Project description:Staphylococcus aureus is a high-priority pathogen causing severe infections with high morbidity and mortality worldwide. Many S. aureus strains are methicillin-resistant (MRSA) or even multi-drug resistant. It is one of the most successful and prominent modern pathogens. An effective fight against S. aureus infections requires novel targets for antimicrobial and antistaphylococcal therapies. Recent advances in whole-genome sequencing and high-throughput techniques facilitate the generation of genome-scale metabolic models (GEMs). Among the multiple applications of GEMs is drug-targeting in pathogens. Hence, comprehensive and predictive metabolic reconstructions of S. aureus could facilitate the identification of novel targets for antimicrobial therapies. This review aims at giving an overview of all available GEMs of multiple S. aureus strains. We downloaded all 114 available GEMs of S. aureus for further analysis. The scope of each model was evaluated, including the number of reactions, metabolites, and genes.Furthermore, all models were quality-controlled using Mᴇᴍᴏᴛᴇ, an open-source application with standardized metabolic tests. Growth capabilities and model similarities were examined. This review should lead as a guide for choosing the appropriate GEM for a given research question. With the information about the availability, the format, and the strengths and potentials of each model, one can either choose an existing model or combine several models to create models with even higher predictive values. This facilitates model-driven discoveries of novel antimicrobial targets to fight multi-drug resistant S. aureus strains.
2022-02-16 | MODEL2007110001 | BioModels
Project description:Staphylococcus aureus is a high-priority pathogen causing severe infections with high morbidity and mortality worldwide. Many S. aureus strains are methicillin-resistant (MRSA) or even multi-drug resistant. It is one of the most successful and prominent modern pathogens. An effective fight against S. aureus infections requires novel targets for antimicrobial and antistaphylococcal therapies. Recent advances in whole-genome sequencing and high-throughput techniques facilitate the generation of genome-scale metabolic models (GEMs). Among the multiple applications of GEMs is drug-targeting in pathogens. Hence, comprehensive and predictive metabolic reconstructions of S. aureus could facilitate the identification of novel targets for antimicrobial therapies. This review aims at giving an overview of all available GEMs of multiple S. aureus strains. We downloaded all 114 available GEMs of S. aureus for further analysis. The scope of each model was evaluated, including the number of reactions, metabolites, and genes. Furthermore, all models were quality-controlled using Mᴇᴍᴏᴛᴇ, an open-source application with standardized metabolic tests. Growth capabilities and model similarities were examined. This review should lead as a guide for choosing the appropriate GEM for a given research question. With the information about the availability, the format, and the strengths and potentials of each model, one can either choose an existing model or combine several models to create models with even higher predictive values. This facilitates model-driven discoveries of novel antimicrobial targets to fight multi-drug resistant S. aureus strains.
2022-02-16 | MODEL2007150001 | BioModels
Project description:Staphylococcus aureus is a high-priority pathogen causing severe infections with high morbidity and mortality worldwide. Many S. aureus strains are methicillin-resistant (MRSA) or even multi-drug resistant. It is one of the most successful and prominent modern pathogens. An effective fight against S. aureus infections requires novel targets for antimicrobial and antistaphylococcal therapies. Recent advances in whole-genome sequencing and high-throughput techniques facilitate the generation of genome-scale metabolic models (GEMs). Among the multiple applications of GEMs is drug-targeting in pathogens. Hence, comprehensive and predictive metabolic reconstructions of S. aureus could facilitate the identification of novel targets for antimicrobial therapies. This review aims at giving an overview of all available GEMs of multiple S. aureus strains. We downloaded all 114 available GEMs of S. aureus for further analysis. The scope of each model was evaluated, including the number of reactions, metabolites, and genes.Furthermore, all models were quality-controlled using Mᴇᴍᴏᴛᴇ, an open-source application with standardized metabolic tests. Growth capabilities and model similarities were examined. This review should lead as a guide for choosing the appropriate GEM for a given research question. With the information about the availability, the format, and the strengths and potentials of each model, one can either choose an existing model or combine several models to create models with even higher predictive values. This facilitates model-driven discoveries of novel antimicrobial targets to fight multi-drug resistant S. aureus strains.
2022-02-16 | MODEL2007150002 | BioModels
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