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Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action

ABSTRACT: Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action

PROVIDER: PRJNA421834 | ENA |

REPOSITORIES: ENA

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Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium marinum]

Project description:Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium marinum]

| PRJNA421833 | ENA

Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium tuberculosis]

Project description:Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium tuberculosis]

| PRJNA421561 | ENA

Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-04-11 | GSE107884 | GEO

Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium marinum]

Project description:Due to the rise of drug resistant forms of tuberculosis there is an urgent need for novel antibiotics to effectively combat these cases and to shorten treatment regimens. Recently, drug screens using whole cell analyses have shown to be successful. However, current high throughput screens focus mostly on stricto sensu life-death screening that give little qualitative information and often require the lengthy process of target and mode of action (MoA) identification. In doing so, promising compound scaffolds or non-optimized compounds that fail to reach inhibitory concentrations are missed. To accelerate early TB drug discovery, we performed RNA sequencing on Mycobacterium tuberculosis and Mycobacterium marinum to map the stress responses that follow upon exposure to sub-inhibitory concentrations of antibiotics with known targets: ciprofloxacin, ethambutol, isoniazid, streptomycin and rifampicin. The resulting dataset comprises the first overview of transcriptional stress responses of mycobacteria to different antibiotics. We show that antibiotics can be distinguished based on their specific transcriptional stress fingerprint i.e. DNA damage for ciprofloxacin and ribosomal stress for streptomycin. Notably, this fingerprint was more distinctive in M. marinum and we decided to use this to our advantage and continue with this model organism. A selection of diverse antibiotic stress genes was used to construct stress reporters. In total, three functional reporters were constructed for DNA damage, cell wall damage and ribosomal inhibition. Subsequently, these reporter strains were used to screen a small anti-TB compound library to predict the mode of action. In doing so we could identify the putative mode of action for three novel compounds, which confirms our approach.

2018-04-12 | GSE107882 | GEO

Accelerating early anti-TB drug discovery by creating mycobacterial indicator strains that predict mode of action [Mycobacterium tuberculosis]

2018-04-12 | GSE107831 | GEO

Accelerating Early Antituberculosis Drug Discovery by Creating Mycobacterial Indicator Strains That Predict Mode of Action.

Project description: Not available

| S-EPMC6021670 | biostudies-literature

Exploring the mode of action of anti-mycobacterial activity of C17 diynes using microarray

Project description:The anti-mycobacterial activity of C17 diynes has been described previously, however, their mode of action remains unknown. Microarray techniques were used to explore the genetic regulation reponses of Mycobacterium smegmatis to treatment with the C17 diynes, falcarinol and panaxydol. Our analyses showed a distinct mode of action of the C17 diynes when compared with commonly used anti-mycobacterial drugs. In addition, geneset enrichment analysis, pathway enrichment analysis and PASS analysis revealed significant gene ontology terms, pathways and potential modes of action, respectively. Combing the results of the three analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis in mycobacteira.

2015-02-23 | GSE64323 | GEO

Exploring the mode of action of anti-mycobacterial activity of C17 diynes using microarray

2015-02-23 | E-GEOD-64323 | biostudies-arrayexpress

Mycobacterial communities in pulmonary NTM

Project description:Profiling Mycobacterial Communities in Pulmonary Nontuberculous Mycobacterial Disease

| PRJEB22153 | ENA

Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection by inducing matrix metalloproteinases

Project description:Mycobacterial arabinogalactan (AG) is an essential cell wall component of Mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Yet, it is unclear whether mycobacterial AG is a pathogen-associated molecular pattern (PAMP) with an elusive pattern recognition receptor (PRR). Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibited cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increased survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacted with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associated with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocked AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravated the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.

2021-02-17 | GSE166850 | GEO

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