Ontology highlight
ABSTRACT:
PROVIDER: PRJNA767551 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The global prevalence of antibacterial resistance requires new antibacterial drugs with novel chemical scaffolds and modes of action. It is also vital to design compounds with optimal physicochemical properties to permeate the bacterial cell envelope. We described an approach of combining and integrating whole cell screening and metabolomics into early antibacterial drug discovery using a library of small polar compounds. Whole cell screening of a diverse library of small polar compounds against <i>Staphylococcus aureus</i> gave compound <b>2</b>. Hit expansion was carried out to determine structure-activity relationships. A selection of compounds from this series, together with other screened active compounds, was subjected to an initial metabolomics study to provide a metabolic fingerprint of the mode of action. It was found that compound <b>2</b> and its analogues have a different mode of action from some of the known antibacterial compounds tested. This early study highlighted the potential of whole cell screening and metabolomics in early antibacterial drug discovery. Future works will require improving potency and performing orthogonal studies to confirm the modes of action.
2021-11-04 | MTBLS788 | MetaboLights
Project description:Pseudopteroxazole (Ptx) and the pseudopterosins are marine natural products with promising antibacterial potential. While Ptx has attracted interest for its anti-mycobacterial activity, pseudopterosins are active against several clinically relevant pathogens. Both compound classes exhibit low cytotoxicity and accessibility to targeted synthesis, yet their antibacterial mechanisms remain elusive. In this study, we investigated the modes of action of Ptx and pseudopterosin G (PsG) in Bacillus subtilis employing an unbiased approach that combines gel-based proteomics with a mathematical similarity analysis of response profiles. Proteomic responses to sublethal concentrations of Ptx and PsG were compared to a library of antibiotic stress response profiles revealing that both induce a stress response characteristic for agents targeting the bacterial cell envelope by interfering with membrane-bound steps of cell wall biosynthesis. Microscopy-based assays confirmed that both compounds compromise the integrity of the bacterial cell wall without disrupting the membrane potential.
2024-01-04 | PXD045994 | Pride
Project description:To determine the transcriptional effects of a novel plant-based compound, dehydrobrachylaenolide, on P. falciparum, parasite cultures were treated with the compound over time. Samples were taken for analysis 2, 6, and 12 hours post-invasion of human red blood cells. Control cultures were treated simultaneously with DMSO, and samples isolated at 2, 6, and 12 hours for transcriptional analysis. Background Antimalarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new antiplasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. Methods Standard phytochemical analysis techniques including solvent-solvent extraction, thin-layer and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallised pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase assay. The effects of treatment on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls) with the pure compound, followed by oligonucleotide microarray and data analysis. Results The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 245.6 nM, which was comparable to the IC50 of chloroquine, against a chloroquine-resistant strain (K1) of P. falciparum. Microarray data analysis identified a cluster of unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. This suggests differentiated modes of action between the two compounds. Conclusions Dehydrobrachylaenolide could play a valuable role as a drug candidate to generate new antimalarial compounds with novel modes of action and favourable ADMET properties.
2011-11-01 | GSE29874 | GEO
Project description:Various bis-benzimidazole derivatives have been reported to possess activity against Gram-positive pathogens. No mechanism of action has been elucidated to fully account for the antibacterial activity of this class of compounds. A group of symmetric bis-benzimidazoles (BBZ) designed as anticancer agents have previously been shown to possess moderate antiproliferative activity. We sought to assess the antibacterial activity and mechanism of action of BBZ compounds against Staphylococcus aureus. Antibacterial activities were assessed by determination of minimal inhibitory concentrations (MICs), time-kill curves, and scanning electron microscopy. Transcriptional responses to BBZ treatment were determined using whole genome microarrays. Activities against bacterial type II topoisomerases were investigated using in vitro supercoiling, decatenation, DNA binding, and DNA cleavage inhibition assays. MICs for EMRSA-16 were between 0.03 and 0.5 μg/mL. The compounds showed concentration-dependent bactericidal activity and induced cell swelling and lysis. Transcriptional responses to BBZ were consistent with topoisomerase inhibition and DNA damage. A subset of BBZ compounds inhibited S. aureus DNA gyrase supercoiling activity with IC50 values in the range of 5−10 μM. This inhibition was subsequently shown to operate through both inhibition of binding of DNA gyrase to DNA and accumulation of single-stranded DNA breaks. We conclude that BBZ compounds are potent antistaphylococcal agents and operate at least in part through DNA gyrase inhibition, leading to the accumulation of single-stranded DNA breaks, and by preventing the binding of gyrase to DNA. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-106]
2012-10-14 | E-BUGS-106 | biostudies-arrayexpress
Project description:High-throughput screening and gene signature analyses frequently identify lead therapeutic compounds with unknown modes of action (MoAs), and the resulting uncertainties can lead to the failure of clinical trials. We developed a multi-omics approach for uncovering MoAs through an interpretable machine learning model of the effects of compounds on transcriptomic, epigenomic, metabolomic, and proteomic data. We applied this approach to examine compounds with beneficial effects in models of Huntington’s disease, finding common MoAs for previously unrelated compounds that were not predicted based on similarities in the compounds’ structures, connectivity scores, or binding targets. We experimentally validated two such disease-relevant MoAs, autophagy activation and bioenergetics manipulation. This interpretable machine learning approach can be used to find and evaluate MoAs in future drug development efforts.
2020-01-22 | GSE129143 | GEO
Project description:High-throughput screening and gene signature analyses frequently identify lead therapeutic compounds with unknown modes of action (MoAs), and the resulting uncertainties can lead to the failure of clinical trials. We developed a multi-omics approach for uncovering MoAs through an interpretable machine learning model of the effects of compounds on transcriptomic, epigenomic, metabolomic, and proteomic data. We applied this approach to examine compounds with beneficial effects in models of Huntington’s disease, finding common MoAs for previously unrelated compounds that were not predicted based on similarities in the compounds’ structures, connectivity scores, or binding targets. We experimentally validated two such disease-relevant MoAs, autophagy activation and bioenergetics manipulation. This interpretable machine learning approach can be used to find and evaluate MoAs in future drug development efforts.
2020-01-22 | GSE129141 | GEO
Project description:Heterotrimeric G proteins mediate crucial and diverse signaling pathways in eukaryotes. To gain insights into the regulatory modes of the G protein and the co-regulatory modes of the G protein and the stress hormone abscisic acid (ABA), we generated and analyzed gene expression in G protein subunit single and double mutants of the model plant Arabidopsis thaliana. Through a Boolean modeling approach, our analysis reveals novel modes of heterotrimeric G protein action. Keywords: transcriptome analysis; G protein subunit mutants; abscisic acid (ABA)
2010-12-06 | GSE19520 | GEO
Project description:Infections associated with antimicrobial-resistant bacteria now represent a significant threat to human health using conventional therapy, necessitating the development of alternate and more effective antibacterial compounds. Silver nanoparticles (Ag NPs) have been proposed as potential antimicrobial agents to combat infections. A complete understanding of their antimicrobial activity is required before these molecules can be used in therapy. Lysozyme coated Ag NPs were synthesized and characterized by TEMEDS, XRD, UV-vis, FTIR spectroscopy, zeta potential, and oxidative potential assay. Biochemical assays and deep level transcriptional analysis using RNA sequencing were used to decipher how Ag NPs exert their antibacterial action against multi-drug resistant Klebsiella pneumoniae MGH78578. RNAseq data revealed that Ag NPs induced a triclosan-like bactericidal mechanism responsible for the inhibition of the type II fatty acid biosynthesis. Additionally, released AgC generated oxidative stress both extra and intracellularly in K. pneumoniae. The data showed that triclosan-like activity and oxidative stress cumulatively underpinned the antibacterial activity of Ag NPs. This result was confirmed by the analysis of the bactericidal effect of Ag NPs against the isogenic K. pneumoniae MGH78578 1soxS mutant, which exhibits a compromised oxidative stress response compared to the wild type. Silver nanoparticles induce a triclosan like antibacterial action mechanism in multi-drug resistant K. pneumoniae. This study extends our understanding of anti-Klebsiella mechanisms associated with exposure to Ag NPs. This allowed us to model how bacteria might develop resistance against silver nanoparticles, should the latter be used in therapy.
2021-01-31 | GSE151953 | GEO
Project description:Alzheimer's disease (AD) drug discovery has rarely been addressed in the context of aging even though sporadic AD accounts for 99% of the cases. Phenotypic screens based upon old age-associated brain toxicities were used to develop the potent AD drug candidates CMS121 and J147. The aim of this project was to investigate whether these two different AD drug candidates prevented the progression of dementia in SAMP8 mice when administered at advanced stages of disease, and whether they shared common modes of action. These transcriptomic data are part of an integrative multi-omics approach that also investigated protein expression, metabolite levels as well as cognition. In addition, in order to further investigate the effect of the drugs in in vitro neuronal cultures, rat primary neurons were treated with the compounds and the transcriptome sequenced.
2019-11-26 | GSE101112 | GEO
Project description:Since chitooligosaccharides are water-soluble, biodegradable and nontoxic compounds, their application may be considered as a promising plant-protecting agent. However, the molecular and cellular modes of action of COs are not yet understood. Transcriptional changes in pea roots treated with COs were investigated via RNA sequencing. Pea roots treated with the deacetylated CO8-DA at low concentration (10-5 М) were harvested 24 h after treatment and their expression profiles were compared against medium-treated control plants. We observed 886 differentially expressed genes (fold change ≥ 1; p-value ˂ 0.05) 24 h after treatment with CO8-DA.
2023-02-23 | GSE218057 | GEO