Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genomic mapping of cAMP receptor protein binding in relation to transcriptional start sites in Mycobacterium tuberculosis

ABSTRACT: In this study we have used ChIPseq analysis to perform comprehensive mapping of the binding profile of the cAMP receptor protein (CRPMt) of M. tuberculosis combined with RNAseq studies to further investigate the transcriptional response following crp gene deletion and under alternative growth conditions.

INSTRUMENT(S): Illumina Genome Analyzer IIx

ORGANISM(S): Mycobacterium tuberculosis

SUBMITTER: Teresa Cortes

PROVIDER: E-MTAB-2390 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Dataset Information

Genomic mapping of cAMP receptor protein binding in relation to transcriptional start sites in Mycobacterium tuberculosis

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