Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1217463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32180600_1.fastq.gz | Fastqsanger.gz | |||
| SRR32180600_2.fastq.gz | Fastqsanger.gz | |||
| SRR32180601_1.fastq.gz | Fastqsanger.gz | |||
| SRR32180601_2.fastq.gz | Fastqsanger.gz | |||
| SRR32180602_1.fastq.gz | Fastqsanger.gz |
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Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1M-bM-^@M-^Ys activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs. Transcriptional profile of TCA1-treated cells relative to DMSO-treated control. Three biological replicates, third is a dye flip.
2013-05-24 | E-GEOD-42151 | biostudies-arrayexpress
Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1’s activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs.
2013-05-24 | GSE42151 | GEO
Project description:EXIT-RIF: Evaluating the Xpert Impact on Tuberculosis – RIFampicin Resistance
| PRJEB57923 | ENA
Project description:We profiled the transcriptional response of different, phylogenetically distinct Mycobacterium tuberculosis (Mtb) strains to isoniazid (INH) and rifampicin (RIF) using RNA-seq. We also hypothesized that an improved Mtb TRN could be inferred using a large, diverse compendium of RNA-seq data and therefore sought to supplement the existing repository of Mtb expression data available on SRA with additional conditions that could inform on Mtb's underlying regulatory programs. We went on to infer Mtb's TRN using a collection of inference methods in combination with this compendium, and employed it to build an interpretable machine learning model of Mtb fitness under stress.
2025-03-19 | GSE292409 | GEO
Project description:Background: Tuberculosis (TB) remains a major public health problem, especially in developing countries, with 1.5 million deaths annually worldwide. Antibiotics are commonly used in the treatment of bacterial infections. As with most drugs, antibiotic treatment can also alter host metabolism, leading to adverse side-effects. Antibiotics can also interfere with the immune system, indirectly through the disturbance of the body’s microbiota or directly by modulating the functions of immune cells. It is therefore important to understand how antibiotic treatment modulates immune cell functions. Here we aim to evaluate the impact of first-line anti-TB drugs on the response of human macrophages infected with Mycobacterium tuberculosis (MTB). Results: Human macrophages were stimulated with heat-killed Mycobacterium tuberculosis (hk-MTB) and treated with isoniazid (INH), rifampicin (RIF), ethambutol, pyrazinamide (PZA) or amikacin (AMK). After 24h of treatment, RNA was collected and we characterized the genome-wide gene expression profiles of drug-treated cells by RNAseq. 556, 752 and 7 genes were differentially expressed in hk-MTB-stimulated macrophages upon RIF, PZA and EMB treatment respectively, whereas in uninfected macrophages, 448 and 11 genes were differentially expressed upon RIF and PZA treatment respectively. No genes were differentially expressed upon INH and AMK treatment. We classified all modulated genes by performing gene-set enrichment analysis. The gene set regulated by PZA in infected macrophages was significantly enriched for genes involved in Integral to lumenal side of endoplasmic reticulum membrane, Cytokine-mediated signaling pathway or Interferon-gamma-mediated signaling pathway. In hk-MTB-stimulated macrophages treated by RIF, we found an enrichment in Endoplasmic reticulum unfolded protein response, NADP binding or Lipid metabolic process. Conclusions: Our results highlight the importance to understand how antibiotic treatment modulates macrophage (Mφ) functions, and more generally, how it impacts the host immune response.
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Project description:The emergence of multidrug resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, resistant to the frontline anti-tubercular drugs rifampicin and isoniazid, forces treatment with less effective and toxic second-line drugs and stands to derail TB control efforts. However, the immune response to MDR Mtb infection remains poorly understood. Here, we determined the RNA transcriptional profile of in vitro generated macrophages to infection with either drug susceptible Mtb HN878 or MDR Mtb W_7642 infection.
2018-12-26 | GSE115495 | GEO
Project description:Iron is critical for the survival of both the host and pathogens. Dysregulated iron metabolism is reported in tuberculosis patients, and therefore represents an opportunity for developing host-directed therapeutics. In this study, antimycobacterial properties of an iron chelator, i.e. Deferoxamine (DFO) and its impact on the transcriptomic changes in Mycobacterium tuberculosis (Mtb) and its impact on limiting host iron in C57BL/6 mice were explored. A group of mice received ferric carboxymaltose to create an iron overload condition and were aerosol infected with H37Rv Mtb. Mtb-infected mice received isoniazid (INH) and rifampicin (RIF) with or without DFO for tissue CFU assay, liver metabolite, iron quantification using GC-MS and ICP-MS, respectively. DFO showed comparable antimycobacterial properties like INH in in-vitro conditions. DFO-treatment deregulated 137 transcript levels in Mtb and majority were involved in stress response, encoding iron-containing proteins and downregulation of genes involved in essential vitamins and amino acid metabolism. Iron-overloaded mice exhibited significantly higher tissue mycobacterial burden at two weeks post-infection and the efficacy of INH and RIF were compromised. Iron chelation by DFO significantly reduced the tissue mycobacterial burden at 4 weeks post-treatment and, as an adjunct to INH and RIF, significantly lowered lung mycobacterial load within the first and second weeks of treatment compared to the group that received only INH and RIF. The intracellular pro-inflammatory cytokine levels in the lung CD4+ T-cells of INH and RIF-treated groups with or without DFO were found to be similar. DFO with RIF and INH treatment significantly altered liver arginine biosynthesis, which has a direct role in neutralizing ammonia and has an immune-supportive role. Currently, DFO is used for treating acute iron toxicity and in iron-overloaded thalassemic patients and holds promise as adjunct therapeutics for tuberculosis.
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Project description:Despite more than a century fighting against tuberculosis, the World Health Organisation has estimated that around 1.7 million people died of tuberculosis in 2016 and over a quarter of the world’s population is infected. One of the critical hurdles for stopping tuberculosis transmission is early and effective diagnosis of patients with the active pulmonary disease. Although important innovations in molecular diagnosis have been recently developed (e.g. Xpert MTB/RIF, Cepheid Inc., USA), there are no suitable tests for population screening at point-of-care. The current tuberculosis diagnosis pipeline presents a highly variable performance and requires access to reference laboratory facilities. A non-sputum based rapid test with high specificity and sensitivity could save ~400,000 lives per year. Therefore, new biomarkers for diagnosis are urgently required for identifying patients with early symptoms and to expedite treatment. Variable sensitivity and specificity can be overcome using a combination of multiple biomarkers (5). Proteins, as ultimate biological effectors, are ideal candidates for diagnostic biomarkers; consequently, proteomic studies are a crucial platform for biomarker discovery in tuberculosis. This work aims to develop a multi-marker panel for tuberculosis diagnosis with high performance capable of differentiating tuberculosis patients from relevant controls. Quantitative Multidimensional Protein Identification Technology (qMudPIT) is applied for biomarker discovery identifying candidates for early diagnosis of tuberculosis. The multidimensional method optimised in this work led to the identification of 5022 plasma proteins and 3577 quantified proteins using iTRAQ labelling. Known and completely novel markers for active tuberculosis in plasma were identified including a peptide derived from Mycobacterium tuberculosis. Complementary statistical and bioinformatic analysis were applied to prioritise candidates for validation in one or two independent cohorts. The plasma proteomic profile here described represents a power strategy for biomarker discovery and the panel proposed has the potential to be translated to a rapid test and which might contribute to tuberculosis control.
2021-09-09 | PXD020212 | Pride