Ontology highlight
ABSTRACT:
PROVIDER: PRJEB32037 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3275160.fastq.gz | Fastqsanger.gz | |||
| ERR3275170.fastq.gz | Fastqsanger.gz | |||
| ERR3275180.fastq.gz | Fastqsanger.gz | |||
| ERR3275190.fastq.gz | Fastqsanger.gz | |||
| ERR3275200.fastq.gz | Fastqsanger.gz |
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Project description:The emergence of multidrug resistant tuberculosis and the increasing level of resistance urges the search for alternative drugs in treatment. Several neuroleptics, like thioridazine, reveal activity against Mycobacterium tuberculosis. Thioridazine was even successfully applied in compassionate therapy of extensively drug resistant tuberculosis in patients when added to other second and third line antibiotics. The synergistic effects between thioridazine and other anti-tuberculosis drugs is usually assigned to the inhibition of efflux pumps by thioridazine. Using an unbiased proteomic approach, we set out to unravel the molecular mechanism of this potential new anti-tuberculosis component by examining the impact of continuous thioridazine exposure on the proteome of M. tuberculosis. We discovered that under the influence of thioridazine several proteins involved in the maintenance of the cell wall permeability barrier are differentially regulated, while none of the known mycobacterial efflux pumps was differentially regulated on the protein level. By assessing accumulation of fluorescent dyes in M. tuberculosis over time, we demonstrated that long-term drug exposure of M. tuberculosis indeed affected the mycobacterial cell envelope and increased the permeability towards both hydrophilic and hydrophobic compounds. Furthermore, we demonstrated that treatment of M. tuberculosis with thioridazine altered the composition of the plasma membrane. Thioridazine induced an increase in cell envelope permeability, and thereby the enhanced uptake of compounds, this could explain the previously reported synergistic effects between thioridazine and other anti-tuberculosis drugs. Although the hypothesis of higher intercellular drug concentrations by THZ has not changed in this study, the more exact knowledge on its mode of action is a major step forward. This new insight in the molecular mechanism of this anti-tuberculosis compound could facilitate further development of this class of drugs for application in drug therapy of multidrug resistant tuberculosis. In fact, the efficacy of many existing drugs could be improved significantly.
2016-07-06 | PXD001208 | 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 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.
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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 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.
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Project description:Multi-drug resistance and latent infection are two major issues in current tuberculosis (TB) control and management. Capreomycin is an important drug used for TB with multi-drug resistance. A recent study also indicates that this drug possesses unique bactericidal activity against non-replicating TB bacilli among known anti-TB drugs. Thus, there is an urgent need for investigating the full-spectrum action of capreomycin. Here we conduct the first microarray-based study on capreomycin using the high-resolution Affymetrix oligonucleotide GeneChip system. The results indicate that capreomycin primarily acts on the information pathways but it also significantly affects cell wall, cell processes, intermediate metabolism and respiration in Mycobacterium tuberculosis. This study not only transcriptionally validates the specific molecular target, 16S rRNA, but also discovers potential new targets of capreomycin, including genes operating at the DNA level, such as Rv0054 (ssb) and Rv3715c (recR), as well as genes involved in cell division like Rv3260c (whiB2). In addition, the nuo gene cluster and the ATP synthase gene cluster are repressed. Keywords: Drug-induced Differential gene expression analysis
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