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Daptomycin tolerance in the Staphylococcus aureus pitA6 mutant is due to upregulation of the dlt-operon

ABSTRACT: It is very important to understand the mechanisms how bacteria become tolerant towards antibiotics during clinical therapy. In a previous study we showed that increased daptomycin (DAP) tolerance of Staphylococcus aureus was due to a point mutation in pitA (inorganic phosphate transporter) that led to intracellular accumulation of both inorganic phosphate (Pi) and polyphosphate (polyP). DAP tolerance in that pitA6 mutant differs from classical resistance mechanisms as there was no increase in minimal inhibitory concentration (MIC). In this study we demonstrate that DAP tolerance in the pitA6 mutant is not triggered by the accumulation of polyP. Transcriptome analysis revealed that about 234 genes were at least 2.0-fold differently expressed in the mutant. Particularly, genes involved in protein biosynthesis, carbohydrate and lipid metabolism as well as in replication and maintenance of DNA were downregulated. However, the most important change was the upregulation of the dlt-operon, which is induced by the accumulation of intracellular Pi. The GraXRS system, known as activator of both dlt and mprF, as well as surface charge, cell wall thickness or the content of wall teichoic acids (WTA) are not involved in DAP tolerance in the pitA6 mutant. In conclusion the DAP tolerance in the pitA6 mutant is due to an upregulation of the dlt-operon triggered directly or indirectly by the accumulation of Pi. WT strain HG003 and its pitA mutant were used to compare transcriptomic changes after 6 or 8 hours of growth in suspension in TSB medium

ORGANISM(S): Staphylococcus aureus

SUBMITTER: FRANCOIS Patrice

PROVIDER: E-GEOD-77069 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Daptomycin tolerance in the Staphylococcus aureus pitA6 mutant is due to upregulation of the dlt-operon

Project description:It is very important to understand the mechanisms how bacteria become tolerant towards antibiotics during clinical therapy. In a previous study we showed that increased daptomycin (DAP) tolerance of Staphylococcus aureus was due to a point mutation in pitA (inorganic phosphate transporter) that led to intracellular accumulation of both inorganic phosphate (Pi) and polyphosphate (polyP). DAP tolerance in that pitA6 mutant differs from classical resistance mechanisms as there was no increase in minimal inhibitory concentration (MIC). In this study we demonstrate that DAP tolerance in the pitA6 mutant is not triggered by the accumulation of polyP. Transcriptome analysis revealed that about 234 genes were at least 2.0-fold differently expressed in the mutant. Particularly, genes involved in protein biosynthesis, carbohydrate and lipid metabolism as well as in replication and maintenance of DNA were downregulated. However, the most important change was the upregulation of the dlt-operon, which is induced by the accumulation of intracellular Pi. The GraXRS system, known as activator of both dlt and mprF, as well as surface charge, cell wall thickness or the content of wall teichoic acids (WTA) are not involved in DAP tolerance in the pitA6 mutant. In conclusion the DAP tolerance in the pitA6 mutant is due to an upregulation of the dlt-operon triggered directly or indirectly by the accumulation of Pi.

2016-02-10 | GSE77069 | GEO

Changes in relative transcript amounts caused by ∆phoU2::kanrpsL+ and double ∆phoU2::kanrpsL+ ∆phoU1::Pcerm mutations in Streptococcus pneumoniae

Project description:Unlike most bacteria, Streptococcus pneumoniae (pneumococcus) has two evolutionarily distinct ABC transporters (Pst1 and Pst2) for inorganic phosphate (Pi) uptake. The genes encoding a two-component regulator (PnpRS) are located immediately upstream of the pst1 operon. Both the pst1 and pst2 operons encode putative PhoU regulators (PhoU1 and PhoU2) at their ends.his study addresses why S. pneumoniae contains dual Pi uptake systems and the regulation and contribution of the Pst1 and Pst2 systems in conditions of high (mM) Pi amount and low (μM) Pi amount. To determine whether PhoU1 or PhoU2 regulates pnpRS, pst1, or pst2 operons. we performed RNA-Seq analyses of ΔphoU2::kanrpsL+ sinlge mutant and ΔphoU2::kanrpsL+ ΔphoU1::Pcerm double mutant compared to the isogenic encapsulated strain cep::kanrpsL+. Unexpectedly, only ΔphoU2::kanrpsL+ indulces the pst1 operon, but not pst2 or pnpRS operon. Addtional PhoU1 deletion has no effect on pst1, pst2, or pnpRS operons.

2017-02-14 | GSE80637 | GEO

A broad response to intracellular long-chain polyphosphate in human cells

Project description:Polyphosphates (polyP) are ancient molecules comprised of inorganic phosphates joined by high energy phosphoanhydride bonds in chains of 3-1000 units in length. In this study, we describe a system to produce polyP in mammalian cells by ectopic expression of the E. coli ppk1+ gene. Production of the EcPpk1 protein results in polyP accumulation throughout the cell, including the nucleus. Using transcriptomic and proteomic analyses, we demonstrate a broad impact of polyP on diverse pathways, including activation of the ERK1/2-EGR1 signaling axis. PolyP accumulation also results in redistribution of several chromatin bound proteins and a translation initiation factor from the nucleus to the cytoplasm. Our work will serve as a novel resource to interrogate polyP biology in higher eukaryotes.

2020-04-22 | GSE149011 | GEO

Staphylococcus aureus

Project description:Daptomycin tolerance in the Staphylococcus aureus pitA6 mutant is due to upregulation of the dlt-operon

| PRJNA309388 | ENA

A broad response to intracellular long-chain polyphosphate in human cells

Project description:Polyphosphates (PolyP) are highly anionic, linear polymers composed of long chains of inorganic phosphates linked together by phosphoanhydride bonds. PolyP chains are found in all kingdoms of life, and play roles in phosphate homeostasis, cell growth, infection, and blood coagulation. Unlike in bacteria and yeast, the mammalian enzymes responsible for the synthesis and degradation of polyP are unknown, which presents a challenge for the study of polyP in higher eukaryotes. To overcome this, we use a system to produce polyP inside of human cells through the ectopic expression of the E. coli Ppk1 synthetic enzyme. Here, we present the results from large-scale transcriptomic and proteomic analyses of polyP producing HEK293T cells. We uncovered >350 RNAs and 14 proteins that show changes following in vivo polyP accumulation. Follow up on specific hits revealed that the internal accumulation of polyP resulted in a significant decrease in the dehydrogenase/reductase DHRS2 without a corresponding increase in p53 phosphorylation, and activation of the ERK1/2-ERG1 signaling axis. Finally, following upregulation of internal polyP we observed the relocalization and redistribution of several nuclear proteins, including chromatin bound proteins DEK, TAF10, GTF2I and the translation initiation factor eIF5b. Altogether, our work serves as a novel resource to understand the impact of increased intracellular polyP in mammalian cells.

2020-09-24 | PXD018896 | 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

Blue light regulates phosphate deficiency-dependent primary root growth inhibition in Arabidopsis

Project description:Plants have evolved mechanisms to improve utilization efficiency or acquisition of inorganic phosphate (Pi) in response to Pi deficiency, such as altering root architecture, secreting acid phosphatases, and activating the expression of genes related to Pi uptake and recycling. Although many genes responsive to Pi starvation have been identified, transcription factors that affect tolerance to Pi deficiency have not been well characterized. We show here that the ectopic expression of B-BOX32 (BBX32) and the mutation of ELONGATED HYPOCOTYL 5 (HY5), whose transcriptional activity is negatively regulated by BBX32, resulted in the tolerance to Pi deficiency in Arabidopsis. The primary root lengths of 35S:BBX32 and hy5 plants were only slightly inhibited under Pi deficient condition and the fresh weights were significantly higher than those of wild type. The Pi deficiency-tolerant root phenotype of hy5 was similarly observed when grown on the medium without Pi. In addition, a double mutant, hy5 slr1, without lateral roots also showed a long primary root phenotype under phosphate deficiency, indicating that the root phenotype of hy5 does not result from increase of external Pi uptake. Moreover, we found that blue light may regulate Pi deficiency-dependent primary root growth inhibition through activating peroxidase gene expression, suggesting the Pi-deficiency tolerant root phenotype of hy5 may be due to blockage of blue-light responses. Altogether, this study points out light quality may play an important role in the regulation of Pi deficiency responses. It may contribute to regulate plant growth under Pi deficiency through a proper illumination.

2019-11-27 | GSE139100 | GEO

Ddp1 cooperates with Ppx1 to counter a stress response initiated by non-vacuolar polyphosphate

Project description:In diverse cells from bacterial to mammalian species, inorganic phosphate is stored in long chains called polyphosphates (polyP). These near universal polymers, ranging from 3 to thousands of phosphate moieties in length, are associated with molecular functions including energy homeostasis, protein folding, and cell signaling. In many cell types, polyphosphate is concentrated in subcellular compartments or organelles. In the budding yeast S. cerevisiae, polyP synthesis by the membrane-bound VTC complex is coupled to its translocation into the lumen of the vacuole, a lysosome-related organelle, where it is stored at high concentrations. In contrast, ectopic expression of bacterial polyphosphate kinase, PPK, results in the toxic accumulation of polyP outside of the vacuole. In this study, we used label-free mass spectrometry to investigate the mechanisms underlying this toxicity. We find that PPK expression results in the activation of a stress response mediated in part by the Hog1 and Yak1 kinases, and Msn2/Msn4 transcription factors. This response is countered by the combined action of the Ddp1 and Ppx1 polyphosphatases that function together to counter polyP accumulation and downstream toxicity. In contrast, ectopic expression of previously proposed mammalian polyphosphatases did not impact PPK-mediated toxicity in the yeast model, suggesting either that these enzymes do not function directly as polyphosphatases in vivo or that they require co-factors unique to higher eukaryotes. Our work provides a mechanistic explanation for why polyP accumulation outside of lysosome-related organelles is toxic. Further, it serves as a resource for exploring how polyP may impact conserved biological processes at a molecular level.

2022-02-04 | PXD031326 | Pride

Comparative Morphophysiological Analyses and Molecular Profiling Reveal ‘Pi-Efficient Strategies’ of a Traditional Rice Genotypefor Low Phosphorus Tolerance in Traditional indica Rice

Project description:Phosphate (Pi) deficiency severely affects crop yield. Modern high yielding rice genotypes are sensitive to Pi deficiency whereas traditional rice cultivars are naturally compatible to low Pi ecosystems. However, the underlying molecular mechanisms for low Pi tolerance in traditional genotypes remain largely elusive. To delineate the molecular mechanisms for low Pi tolerance, two contrasting rice genotypes - Dular (low Pi tolerant) and PB1 (low Pi sensitive) - have been selected. Comparative morphophysiological, global transcriptome and lipidome analyses of root and shoot tissues of both genotypes raised under Pi deficient and sufficient conditions revealed the potential low Pi tolerance mechanisms of traditional genotype. Most of the genes associated with enhanced internal Pi utilization (phospholipid remobilization) and modulation of root system architecture (RSA) are highly induced in traditional rice genotype, Dular. Higher reserve of phospholipid and greater accumulation of galactolipids under low Pi in Dular indicated its better internal Pi utilization. Furthermore, Dular also maintained better root growth than PB1 under low Pi resulting in larger root surface area due to increased lateral root density and root hair length. Genes involved in enhanced low Pi tolerance of traditional genotype can be exploited to improve the low Pi tolerance of modern high yielding rice cultivars.

2016-01-29 | GSE74795 | GEO

Escherichia coli O157:H7 responds to phosphate starvation by modifying LPS involved in biofilm formation

Project description:Pathogens like E. coli O157:H7 are responsible for many outbreaks and can be found and survive in poor inorganic phosphate (Pi) environments. In E. coli the phosphate homeostasis is regulated by the Pst system and the two-component system PhoB/R. In a Δpst mutant, PhoB is constitutively activated and biofilm formation is increased. To understand how PhoB activation lead to biofilm increase, we compared the transcriptomes of EDL933 the WT strain and Δpst mutant both grown in MOPS Pi rich medium, using the Affymetrix GeneChip® E. coli Genome 2.0 Array.

2019-01-23 | GSE125488 | GEO

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