Responses of Pseudomonas aeruginosa to last resort antibiotics
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PROVIDER: PRJEB41029 | ENA |
REPOSITORIES: ENA
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Project description:Responses of Pseudomonas aeruginosa to last resort antibiotics monitored by transcriptome and translatome analyses
| PRJEB41027 | ENA
Project description:This study aims to determine the epidemiology of Enterobacteriaceae resistant to antibiotics of last resort in pregnant women in labour at a tertiary hospital, Pretoria, South Africa. Rectal swabs shall be used to screen for colonisation with CRE and colistin-resistant Enterobacteriales in pregnant women during labour. Carbapenem and colistin-resistant Enterobacterales can cause the following infections: bacteraemia; nosocomial pneumonia; urinary tract infections, and intra-abdominal infections. Due to limited treatment options, infections caused by these multidrug-resistant organisms are associated with a mortality rate of 40-50%. Screening for colonisation of carbapenem-resistant Enterobacteriaceae (CRE) and colistin-resistant Enterobacteriaceae will help implement infection and prevention measures to limit the spread of these multidrug-resistant organisms.
2022-07-20 | GSE208573 | GEO
Project description:Background: Pseudomonas aeruginosa often causes multidrug-resistant infections in immunocompromised patients and polymyxins are often used as the last-line therapy. Alarmingly, resistance to polymyxins has been increasingly reported worldwide recently. To rescue this last-resort class of antibiotics, it is necessary to systematically understand how P. aeruginosa alters its metabolism in response to polymyxin treatment, thereby facilitating the development of effective therapies. To this end, a genome-scale metabolic model (GSMM) was employed to analyse bacterial metabolic changes at the systems level. Findings: A high-quality GSMM iPAO1 was constructed for P. aeruginosa PAO1 for antimicrobial pharmacological research. Model iPAO1 encompasses an additional periplasmic compartment and contains 3,022 metabolites, 4,265 reactions and 1,458 genes in total. Growth prediction on 190 carbon and 95 nitrogen sources achieved an accuracy of 89.1%, outperforming all reported P. aeruginosa models. Notably, prediction of the essential genes for growth achieved a high accuracy of 87.9%. Metabolic simulation showed that lipid A modifications associated with polymyxin resistance exert a limited impact on bacterial growth and metabolism, but remarkably change the physiochemical properties of the outer membrane. Modelling with transcriptomics constraints revealed a broad range of metabolic responses to polymyxin treatment, including reduced biomass synthesis, upregulated amino acids catabolism, induced flux through the tricarboxylic acid cycle, and increased redox turnover. Conclusions: Overall, iPAO1 represents the most comprehensive GSMM constructed to date for Pseudomonas. It provides a powerful systems pharmacology platform for the elucidation of complex killing mechanisms of antibiotics.
2018-02-28 | MTBLS630 | MetaboLights
Project description:Antibiotics in low concentrations may have an array of effects. We have exposed growing P. aeruginosa cells to different classes of antibiotics in order to investigate this hypothesis. We have used DNA microarrays to investigate the effect of low concentrations of antibiotics (azithromycin, ceftazidime and ciprofloxacin) on the gene expression of P. aeruginosa aiming to elucidate general trends. Keywords: Treatment with antibiotics
2008-02-28 | GSE8953 | GEO
Project description:Circumventing or overwhelming the bacterial adaptation capabilities is key to combatting multidrug-resistant pathogens like Pseudomonas aeruginosa. In an effort to understand the physiological response of P. aeruginosa to clinically relevant antibiotics, we investigated the proteome after exposure to ciprofloxacin, levofloxacin, rifampicin, gentamicin, tobramycin, azithromycin, tigecycline, polymyxin B, colistin, ceftazidime, meropenem, and piperacillin/tazobactam. We further investigated the response to CHIR-90, which represents a promising class of lipopolysaccharide biosynthesis inhibitors currently under evaluation. Radioactive pulse-labeling of newly synthesized proteins followed by 2D-PAGE was used to monitor the acute response of P. aeruginosa to antibiotic treatment. Marker proteins were excised from non-radioactive gels and identified by mass spectrometry. The proteomic profiles provide insights into the cellular defense strategies for each antibiotic. A mathematical comparison of these response profiles based on upregulated marker proteins revealed similarities of responses to antibiotics acting on the same target area.
2021-11-29 | PXD029948 | Pride
Project description:Circumventing or overwhelming the bacterial adaptation capabilities is key to combatting multidrug-resistant pathogens like Pseudomonas aeruginosa. We investigated the physiological stress exerted by approved antibiotics (ciprofloxacin, levofloxacin, rifampicin, gentamicin, tobramycin, azithromycin, tigecycline, polymyxin B, colistin, ceftazidime, meropenem, piperacillin/tazobactam), experimental antibiotics (CHIR-090) and NSAIDs (acetylsalicylic acid (aspirin), diclofenac, ibuprofen), and studied the bacterial response on the proteome level. Radioactive pulse-labeling of newly synthesized proteins followed by 2D-PAGE was used to monitor the acute response of P. aeruginosa to antibiotic treatment. Subsequently, marker proteins were excised from non-radioactive gels and identified by mass spectrometry. We generated a reference library of P. aeruginosa proteomic responses and implemented a mathematical comparison of the profiles. Proteomic signatures were derived for clinically relevant target areas.
2022-08-12 | PXD022879 | Pride
Project description:The emergence of colistin resistance in carbapenem-resistant and extended-spectrum ß-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in several polymyxin-resistant, ESBL-producing, carbapenem resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including a ‘next generation’ polymyxin derivative, FADDI-287. To gain additional insight into the potential mechanism of action of PBT2, we analyzed the transcriptome of K. pneumoniae and E. coli in the presence of sub-inhibitory concentrations of PBT2. Treatment with PBT2 was associated with multiple stress responses in both K. pneumoniae and E. coli. Significant changes in the transcription of transition metal ion homeostasis genes were observed in both strains.
2019-06-13 | GSE132637 | GEO
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
Project description:The design of novel antibiotics that break antimicrobial resistance relies on a profound understanding of their mechanism of action. While it has been shown that the cellular effects of antibiotics cluster according to their molecular targets, we investigated whether compounds binding to different sites of the same target can be differentiated by their transcriptome or metabolome signatures. The effects of three fluoroquinolones, two aminocoumarins and two cystobactamids, all inhibiting bacterial gyrase, on Pseudomonas aeruginosa at sub-inhibitory concentrations were captured by RNA sequencing.
2021-05-03 | GSE166602 | GEO
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