Expression profiling of extensively drug-resistant tuberculosis isolates and H37Rv exposed to anti-TB compounds
Ontology highlight
ABSTRACT:
ORGANISM(S): Mycobacterium tuberculosis
SUBMITTER: Yu Guohua
PROVIDER: E-GEOD-53843 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:To explore the mechanism of drug resistance, most works focused on resistance associated genetic mutations, whereas concerns for resistance related gene expression are relatively low. Here a global expression analysis was performed between a reference strain H37Rv and two clinical extensively drug-resistant (XDR) strains with three anti-TB drug exposures {isoniazid (INH), capreomycin (CAP), rifampicin (RIF)}
2014-01-07 | GSE53843 | 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:Isoniazid (INH) is the first-line anti-tuberculosis drug used for nearly seventy years. Metabolites of INH showed hepatotoxicity in human and tumorigenicity in rodents. However, mechanism underlying the side effects of INH is elusive. Histone acylation is known to be modulated by intracellular metabolites. Here, we report INH and its metabolites induces a novel post-translational modification (PTM) on histones, the lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH functions as a donor to promote biosynthesis of isonicotinyl-CoA that is used for a co-factor of intracellular isonicotinylation reaction. Twenty-six isonicotinylation sites were identified on histones in HepG2 cells by mass spectrometry. Acetyltransferases CREB-binding protein (CBP) and P300 were found to catalyze histone Kinic, whilst histone deacetylase HDAC3 functions as a deisonicotinylase. MNase sensitivity assay and RNA-seq analysis showed that histone Kinic relaxes chromatin structure and promotes gene transcription. Importantly, INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates PI3K/Akt/mTOR signaling pathway in liver cancer cells, linking INH to the tumorigenicity in liver. Further, Kinic was found increased in liver cancer patients with concomitant raised PIK3R1 protein level. In addition, histone Kinic also affects TNF and GABAergic synapse signaling pathways that are closely related to INH-caused side effects. Taken together, we demonstrated that lysine isonicotinylation represents the first histone acylation mark with the pyridine ring that may arise broad biological effects. Therefore, INH-induced isonicotinylation is likely a mechanism accounting for side effects in patients who taking long-term INH for anti-tuberculosis therapy and this modification may also increase cancer risk in human.
2021-08-20 | PXD025490 | Pride
Project description:The inh-alpha/Tag mouse is a murine adrenocortical tumor model that combines gonadotropin-dependent tumorigenesis with SV40Tag expression (which inhibits p53). These mice have been extensively used to study adrenocortical and gonadal tumorigenesis, as they initially present with gonadal tumors. To induce adrenocortical tumorigenesis, the inh-alpha/Tag mice need to be prebubertally gonadectomized. Generally, females develop adrenal tumors faster and larger in size than males, with a very high individual variations of tumor volume and histological appearance. In this study, we used the inh-alpha/Tag mouse model to analyze the molecular basis of the LH-dependent adrenal tumorigenesis. Experimental inh-alpha/Tag and control littermates (C57Bl/6N) mice of both sexes were used as the animal model. inh-alpha/Tag and WT mice were gonadectomized at 21-24 days of age. Mice were sacrificed at the age of 30 weeks (+/-1 week) and adrenals snap-frozen in liquid nitrogen for microarray analysis. Additionally, a group of 27 week-old inh-alpha/Tag mice (+/-1 week) were treated for 3 weeks with GnRH antagonist cetrorelix acetate (#C5249, Sigma-Aldrich) (3mg/kg/48h). Mice were sacrificed at the age of 30 weeks (+/-1 week) and adrenals snap-frozen in liquid nitrogen for microarray analysis.
2017-02-01 | E-MTAB-5310 | 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 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:The Raf kinase inhibitor protein (RKIP) is a dual inhibitor of the Raf kinase and the G-protein-coupled receptor kinase 2 (GRK2). GRK2 is an indispensable kinase, which exerts a major role in the pathogenesis of heart failure, and inhibition of GRK2 is cardioprotective in experimental models of heart failure. To investigate the cardiac function of RKIP as GRK2 inhibitor, we generated transgenic mice with myocardium-specific expression of RKIP under control of the alpha-MHC promoter. For comparison, mice with myocardium-specific expression of a GRK-specific peptide inhibitor (GRK-Inh) were also generated. Two different transgenic mouse models were established. Transgenic RKIP mice and transgenic GRK-Inh mice were born at Mendelian frequencey and grew to adulthood normally. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) RKIP-transgenic mice, (ii) GRK-Inh-transgenic mice, and (iii) B6 control mice.
2012-12-06 | E-GEOD-42753 | 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:Understanding emergence of drug resistance in pathogens systematically is a major challenge. To address this issue, lab-evolved strain resistant to first-line tuberculosis drug, isoniazid (INH), was analysed. Transcriptome analysis of different conditions revealed genes that are differentially regulated in wild-type (WT) and isoniazid resistant (2XR and 4XR) strains. Microarray analysis was performed for WT, sub-MIC, 2XR and 4XR strains of Mycobacterium smegmatis. Overall, the numbers of DEGs observed are 1529 in sub-MIC (596 - up, 933 - down), 1381 (899 – up, 482 – down) in 2XR and 716 in 4XR (267 – up, 449 – down) conditions. 52 of them are seen to be up-regulated across all drug concentrations as compared to WT while 185 are seen to be down-regulated in all. Transcriptome analysis revealed that there are variations in gene expression pattern in the resistant strains as compared to WT strain. This indicates that differential regulation of genes is, in some way, responsible for conferring the phenotype to the organism.
2014-12-13 | GSE64132 | GEO
Project description:Endometrial receptivity is imperative to achieving pregnancy in humans. A disruption in the development of endometrial receptivity is responsible for recurrent implantation failures (RIF) of endometrial origin. To further understand the molecular mechanisms behind the endometrial receptivity process, we used the 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) method to compare and quantify the proteomes from endometrial biopsies of three different endometrial statuses (fertile women, IUD carriers and RIF patients). Overall, iTRAQ allowed to identify 1,889 non-redundant proteins. Of these, 188 were differentially expressed proteins (DEP) (p-value < 0.05) among the three endometrial groups. Pairwise comparisons revealed 133 significant DEP in fertile vs. IUD carriers and 158 DEP in RIF vs. IUD carriers. However, no DEP were identified between fertile and RIF patients. Western blot validation of three DEP involved in endometrial receptivity (Plastin 2, Lactotrasferrin, and Lysozyme) confirmed our iTRAQ results. Moreover, functional KEGG enrichment revealed that complement and coagulation cascades and peroxisome were the two most significant pathways for the RIF vs. IUD comparison and ribosome and spliceosome for the fertile vs. IUD comparison, as possible important pathways involved in the endometrial receptivity acquisition. Our findings confirm that an IUD introduces numerous changes in the endometrial protein profile when compared to fertile and RIF endometria, revealing some key proteins involved in endometrial receptivity. The lack of DEP between fertile and RIF patient endometria suggest either that idiopathic RIF may not have an endometrial origin, with other as-yet-unknown factors involved.
2019-11-06 | PXD011094 | Pride
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