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ABSTRACT:
PROVIDER: PRJNA1215569 | ENA |
REPOSITORIES: ENA
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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: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:EXIT-RIF: Evaluating the Xpert Impact on Tuberculosis – RIFampicin Resistance
| PRJEB57923 | ENA
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:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis
2015-03-31 | E-GEOD-67427 | biostudies-arrayexpress
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug Rifampicin. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
2021-12-15 | GSE166622 | GEO
Project description:“Viable but non-culturable” (VBNC) states pose challenges for environmental and clinical microbiology, but their biological mechanisms remain obscure. Mycobacterium tuberculosis (Mtb), the leading cause of death from infection until COVID-19, affords a striking example. Mtb can enter into a “differentially detectable” (DD) state associated with phenotypic antimicrobial resistance in which Mtb cells are viable but undetectable as colony-forming units. We found that Mtb cells enter the DD state when they undergo sublethal oxidative stress that damages their DNA, proteins, and lipids, and in addition, their replication is delayed, allowing repair. Mycobacterium bovis and BCG fail to enter the DD state under similar conditions. These findings have implications for TB latency, detection, relapse, treatment monitoring, and development of regimens that overcome phenotypic antimicrobial resistance.
2021-11-24 | GSE180792 | GEO