C-di-AMP Metabolism in S. aureus
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB14723 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1519880_1.fastq.gz | Fastqsanger.gz | |||
| ERR1519880_2.fastq.gz | Fastqsanger.gz | |||
| ERR1519881_1.fastq.gz | Fastqsanger.gz | |||
| ERR1519881_2.fastq.gz | Fastqsanger.gz | |||
| ERR1519882_1.fastq.gz | Fastqsanger.gz |
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Project description:Cyclic-di-adenosine monophosphate (c-di-AMP) is required for osmotic regulation in Staphylococcus aureus but dispensable for viability in anaerobic conditions
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Project description:The obligate intracellular bacterium Chlamydia alternates between two functional forms during its developmental cycle: elementary body (EB) and reticulate body (RB). However, the molecular mechanisms governing the transitions between these forms are unknown. Here, we present evidence cyclic di-AMP (c-di-AMP) is a key factor in triggering the transition from RB to EB (i.e., secondary differentiation) in the chlamydial developmental cycle. We made strains producing different levels of c-di-AMP, which we linked to changes in secondary differentiation status. Increases in c-di-AMP resulted in an earlier increase in transcription of EB-associated genes, and this was further manifested in earlier production of EBs. In contrast, when c-di-AMP levels were decreased, secondary differentiation was delayed. Based on these data, we conclude there is a threshold level of c-di-AMP needed to trigger secondary differentiation in Chlamydia. This is the first study to define a mechanism of secondary differentiation in Chlamydia.
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Project description:Streptococcus pneumoniae harbors two cyclic di-AMP (c-di-AMP) phosphodiesterases Pde1 and Pde2. Previously, we demonstrated that deletion of one or both of these proteins leads to growth retardation in culture media, defects in the bacterial stress response, and attenuation in mouse models of disease. All of these phenotypes are due to increased levels of c-di-AMP, since the nature and break down products of each protein are different, and mutations that lower c-di-AMP levels partially restore growth and stress tolerance in these mutants. However, how c-di-AMP mediates pneumococcal stress resistance and virulence is unknown. To establish how c-di-AMP affects the transcriptome, RNA-Seq analysis was employed to compare gene expression between wild-type and Δpde1Δpde2 (ST2734) pneumococci. Overall, the competence regulon was upregulated in the Δpde1Δpde2 mutant.
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Project description:Cyclic di-AMP is an essential second messenger in many Gram-positive bacteria, including the model organism Bacillus subtilis. Here, we analyzed the transcriptome of a strain accumulating c-di-AMP in vivo. Our results demonstrate that accumulation of c-di-AMP affects the expression of several hundred genes, among them many mother-cell specific sporulation genes. Additionally, the two major biofilm operons, epsA-O and tapA-sipW-tasA, are affected. High levels of c-di-AMP abolish transcription of genes responsible for biofilm formation which in turn leads to a defect in complex colony formation in B. subtilis.
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Project description:Cyclic di-AMP drives secondary differentiation in Chlamydia trachomatis
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Project description:Second messenger nucleotides such as c-di-AMP are produced by bacteria in response to environmental stimuli and can contribute to the regulation of a number of cellular processes including osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. Here, as part of an effort to uncover the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis, we utilized high-throughout RNA Sequencing analysis to explore the impact of deletion of genes responsible for c-di-AMP synthesis (cdaA) and degradation (dhhP and gdpP).
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Project description:The bacterial second messenger c-di-AMP controls various cellular processes including potassium and osmolyte homeostasis. The c-di-AMP receptor protein DarB of Bacillus subtilis binds to the Rel protein and triggers the Rel-dependent stringent response. Here we report crystal structures of DarB in the ligand-free state and of DarB complexes with c-di-AMP, 3´3´-cGAMP and AMP. DarB consists of two CBS domains and forms a homo-dimer with a parallel, head-to-head assembly of the monomers. The DarB dimer binds two cyclic di-nucleotide molecules or two AMP molecules. Only one adenine of bound c-di-AMP is specifically recognized by DarB, while the second one protrudes out of the donut-shaped protein. This enables DarB to bind also 3´3´-cGAMP, as only the adenine fits to the active site, but not the guanine. In absence of c-di-AMP DarB binds to Rel and stimulates (p)ppGpp synthesis, whereas the presence of c-di-AMP abolishes the interaction. The DarB crystal structures reveal no conformational changes upon c-di-AMP binding, hence, the regulatory function of DarB on Rel must be controlled directly by the bound c-di-AMP. A structural model of the DarB-Rel complex was erived from in silico docking, validated with a mass spectrometric analysis of the chemically cross-linked DarB-Rel complex and mutagenesis studies. Based on the predicted complex structure a mechanism of stringent response regulation by c-di-AMP is suggested.
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Project description:Streptococcus agalactiae is among the few pathogens that have not developed resistance to ß-lactam antibiotics despite decades of clinical use. The molecular basis of this long-lasting susceptibility has not been investigated, and it is uncertain whether specific mechanisms constraint the emergence of resistance. In this study, we first report a conserved role of the signaling nucleotide cyclic-di-AMP in the sensitivity of S. agalactiae to ß-lactam. Specifically, we demonstrate that inactivation of the phosphodiesterase GdpP confers ß-lactam tolerance. Characterizing the signaling pathway revealed an antagonistic regulation by the transcriptional factor BusR, which is activated by c-di-AMP and negatively regulates ß-lactam susceptibility. Furthermore, we show that simultaneous inhibition of osmolyte transporters activity and transcription by c-di-AMP has an additive effect, sustaining ß-lactam tolerance. Finally, transposon mutagenesis for ß-lactam reduced susceptibility reveals a convergent pattern of mutations, including in the KhpAB small RNA chaperone and the protein S immunomodulator. Overall, our findings suggest mechanisms that may foster antibiotic resistance in S. agalactiae and demonstrate that c-di-AMP acts as a turgor pressure rheostat, coordinating an integrated response to cell wall weakening due to ß-lactam activity.
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