Transcriptional profiling of M. tuberculosis treated with DG167 and INH
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ABSTRACT:
PROVIDER: PRJNA507615 | ENA |
REPOSITORIES: ENA
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Project description:Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance. Data is also available from <ahref=http://bugs.sgul.ac.uk/E-BUGS-104 target=_blank>BuG@Sbase</a>
2011-01-17 | E-BUGS-104 | biostudies-arrayexpress
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.
2020-04-29 | GSE143731 | GEO
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:Transcriptional profiling of Mycobacterium tuberculosis CDC1551 comparing control butyric acid-treated cells with 20mM db-cAMP treated cells after 2hrs of treatment with shaking at 200rpm at 37C.
2014-01-23 | GSE54289 | GEO
Project description:We report that combined treatment with both DG167 and INH activates a cellular response associated with loss of persistence and induction of cidality that is distinct from the cellular response induced by single drug treatment.
2018-11-30 | GSE123132 | GEO
Project description:Out of the 10 million of tuberculosis (TB) cases estimated in the world, around 14% are isoniazid (INH) resistant among new cases and 29% among previously treated cases in the last decade. INH is one of the oldest but also one of the more potent drugs to eliminate Mycobacterium tuberculosis (Mtb), the causing agent of TB. Because of the efficiency of isoniazid (INH) against Mycobacterium tuberculosis (Mtb), many studies are still focused in better understand its role in different bacterial metabolic pathways. We recently conducted a study that evaluated the changes in the protein abundance at different cellular fractions when clonal strains of Mtb developed INH resistance in the clinical and laboratory setting. Here, we want to establish which of the protein changes occurred or started because of the initial exposure to INH. Additionally, we wanted to evaluate if those changes happen differently in strains that are sensitive or resistant to INH, evaluating different cellular compartments from two different genetic lineages of Mtb. For this purpose, we analyzed the proteome of each cellular compartment (cytosol, cell wall, membrane and secreted proteins) through liquid chromatography (nano-HPLC) coupled to mass spectrometry using the Orbitrap Velos instrument and a t-test to perform the statistical analysis for each pair comparison.
2019-06-17 | PXD007588 | Pride
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:Transcriptional profiling of Mycobacterium tuberculosis H37Rv strains comparing control DMSO treated strains with Linezolid treated strains. Goal was to determine the effects of Linezolid against Mycobacterium tuberculosis H37Rv strains.
2011-10-11 | GSE32718 | GEO
Project description:Transcriptional profiling of Mycobacterium tuberculosis H37Rv strains comparing control DMSO treated strains with Lupulone treated strains. Goal was to determine the effects of Lupulone against Mycobacterium tuberculosis H37Rv strains.
2011-08-30 | GSE31732 | GEO
Project description:We sought to identify pathways dysregulated in Mycobacterium tuberculosis upon treatment with the compound C10. We treated M. tuberculosis with DMSO, 5 μM C10, or 25 μM C10 for 48 hours in Sauton's medium and used RNA-sequencing to compare transcriptional profiles.
2019-05-31 | GSE129833 | GEO