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Accumulation of inorganic polyphosphate mediates metabolic downshift and antibiotic tolerance in Mycobacterium tuberculosis

ABSTRACT: The stringent response, involving the regulatory molecules inorganic polyphosphate (poly P) and (p)ppGpp, is believed to mediate Mycobacterium tuberculosis persistence. In this study, we identified a novel exopolyphosphatase responsible for poly P hydrolysis. Using two different poly P-accumulating M. tuberculosis recombinant strains, we found that increased poly P content drives the organisms into early growth arrest, and contributes to tolerance to the cell wall-active agent isoniazid, increased resistance to stress conditions, and improved survival in macrophages. Transcriptomic and metabolomics analysis revealed metabolic downshift manifested by reduced expression of the transcriptional and translational machinery, and shift from utilization of glucose as a carbon source. In summary, regulation of the poly P balance is critical for persister formation in M. tuberculosis.

ORGANISM(S): Mycobacterium tuberculosis CDC1551

PROVIDER: GSE57868 | GEO | 2015/02/20

SECONDARY ACCESSION(S): PRJNA248293

REPOSITORIES: GEO

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Accumulation of inorganic polyphosphate mediates metabolic downshift and antibiotic tolerance in Mycobacterium tuberculosis

Project description:The stringent response, involving the regulatory molecules inorganic polyphosphate (poly P) and (p)ppGpp, is believed to mediate Mycobacterium tuberculosis persistence. In this study, we identified a novel exopolyphosphatase responsible for poly P hydrolysis. Using two different poly P-accumulating M. tuberculosis recombinant strains, we found that increased poly P content drives the organisms into early growth arrest, and contributes to tolerance to the cell wall-active agent isoniazid, increased resistance to stress conditions, and improved survival in macrophages. Transcriptomic and metabolomics analysis revealed metabolic downshift manifested by reduced expression of the transcriptional and translational machinery, and shift from utilization of glucose as a carbon source. In summary, regulation of the poly P balance is critical for persister formation in M. tuberculosis. The transcriptome of poly P accumulation strains, Rv1026 knock-down and ppk1 knock-in were compared to empty vector strains by RNA-seq.

2015-02-20 | E-GEOD-57868 | biostudies-arrayexpress

Transcriptome analysis of Escherichia coli mutants involved in inorganic polyphosphate metabolism

Project description:Inorganic polyphosphate (Poly P) is a polymer of various phosphate residues linked by phosphoanhydride bonds as in ATP. It is found in all cells in nature with roles in the origin and survival of species, particularly in bacteria. To study the role of the inorganic polyphosphate in bacteria, we obtained knockout mutants of polyP metabolism genes in Escherichia coli K12. We performed DNA microarray experiments of single mutants in polyphosphate kinase 1 (PPK1), exopolyphosphatase (PPX) and also with the double mutant (PPK1 and PPX). The mutant strains growth normally in LB medium but have different colony morphology phenotypes. All mutants have flagellation problems and a detail description of all gain and lost phenotypes o these strains will be published soon because we performed a complete phenotypic microarray study of all three mutant strains.

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Oxygen downshift experiment with E.coli W3110

2008-07-08 | GSE12006 | GEO

Global proteomic profile of antibiotic induced persistent Mycobacterial sapmles

Project description:Global protein alteration in Mycobacterium tuberculosis H37 RV ( Mtb-H37RV) of day 2 (control) and day 16 (persistent) samples (in duplicates) treated with antibiotics 8µg/ml of ciprofloxacin and 0.1 µg/ml of Isoniazid (to mimic persister stage) were accessed using 4 plex iTRAQ label.

2021-07-29 | PXD013621 | Pride

Understanding the roles of dksA and greA in inorganic polyphosphate accumulation in Escherichia coli

Project description:Inorganic polyphosphate (polyP) is synthesized by bacteria in response to various stresses, but the mechanism of its regulation is unknown. Mutants of Escherichia coli lacking the RNA polymerase-binding transcription factor dksA are defective in polyP synthesis after a nutrient limitation stress, and this defect is reversed in a dksA greA mutant. In this work, we used RNA sequencing to compare transcription in wild-type, dksA, and dksA greA strains of E. coli before and after nutrient limitation, to identify genes whose expression pattern correlates with ability to synthesize polyP.

2020-03-11 | GSE144816 | GEO

Polyphosphate Metabolic Gene Expression Analyses Reveal Mechanisms of Phosphorus Accumulation and Release in Microlunatus phosphovorus Strain JN459

Project description:The ability of Microlunatus phosphovorus to accumulate large amounts of polyphosphate (Poly-P) plays an important role in removing soluble phosphorus from wastewater. Our analyses indicate that Microlunatus phosphovorus accumulates Poly-P under aerobic conditions but releases phosphorus under anaerobic conditions. To determine the mechanisms underlying Poly-P metabolism, we compared transcriptional profiles under aerobic and anaerobic conditions. Significant differences were detected in the expression levels of genes associated with Poly-P metabolism between aerobic and anaerobic conditions. These findings enhance our understanding of phosphate metabolism in a major bacterial species involved in wastewater phosphorus reduction.

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Transcription profiling of E.coli W3110 oxygen downshift

Project description:Dynamical response to oxygen downshift under fermentation conditions was tested by taking sample before (S1) and after (S2, S3 and S4) the oxygen downshift. The dynamical changes relevant for ongoing research on physiology were applied. Experiment Overall Design: Four microarray chips were analyzed: Experiment Overall Design: S1 was taken 15 min before the oxygen downshift Experiment Overall Design: S2, S3 and S4 were taken 15 min, 45 min and 75 min after the oxygen downshift, respectively

2008-10-21 | E-GEOD-12006 | biostudies-arrayexpress

Mycobacterium tuberculosis CDC1551

Project description:Accumulation of inorganic polyphosphate mediates metabolic downshift and antibiotic tolerance in Mycobacterium tuberculosis

| PRJNA248293 | ENA

Effect of addition of cysteine to isoniazid treatment of Mycobacterium tuberculosis

Project description:Transcriptional profiling of Mycobacterium tuberculosis H37Rv after 4 hours of combination isoniazid and cysteine treatment relative to treatment with isoniazid alone.

2017-03-27 | GSE86184 | GEO

Gene expression analysis of Mycobacterium tuberculosis high-persister (hip) mutants.

Project description:Bacterial persister cells are phenotypic variants of regular cells that are tolerant to antibiotics. High-persister (hip) mutants of Mycobacterium tuberculosis produce 10- to 1,000-fold more persister cells than the wild type strain when challenged with various antibiotics. Comparison of gene expression pattern of the hip mutants may provide clues as to the genetic mechanisms underlying persister formation. Transcriptome analysis will provide information on what differentiates M. tuberculosis hip strains from regular strains, which will be useful in the development of anti-persister therapy for persister cell eradication. Twelve independent M. tuberculosis hip mutants and the wild type strain were grown to stationary phase in duplicate. To avoid analyzing the drug effect, total RNA was extracted from the cultures prior to the addition of antibiotic for hybridization to Affymetrix microarrays. Data analysis was performed by comparing the hip mutants to the wild type control.

2014-04-07 | E-GEOD-55647 | biostudies-arrayexpress

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