Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis of novel ligands targeting phenazine biosynthesis proteins as a strategy for antibiotic intervention.

ABSTRACT:

Abstract

In this contribution, we report synthetic strategies towards potential ligands for the study of binding differences between PhzE, the first enzyme in the biosynthesis of phenazines, and the related enzyme anthranilate synthase. The ligands were designed with the overriding goal to develop new antibiotics via downregulation of phenazine biosynthesis.

Graphical abstract

SUBMITTER: Guttenberger N

PROVIDER: S-EPMC5906492 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis of novel ligands targeting phenazine biosynthesis proteins as a strategy for antibiotic intervention.

Guttenberger Nikolaus N Schlatzer Thomas T Leypold Mario M Tassoti Sebastian S Breinbauer Rolf R

Monatshefte fur chemie 20171130 4

<h4>Abstract</h4>In this contribution, we report synthetic strategies towards potential ligands for the study of binding differences between PhzE, the first enzyme in the biosynthesis of phenazines, and the related enzyme anthranilate synthase. The ligands were designed with the overriding goal to develop new antibiotics via downregulation of phenazine biosynthesis.<h4>Graphical abstract</h4> ...[more]

PMID: 29681660

Similar Datasets

Pip, a novel activator of phenazine biosynthesis in Pseudomonas chlororaphis PCL1391.

Project description:Secondary metabolites are important factors for interactions between bacteria and other organisms. Pseudomonas chlororaphis PCL1391 produces the antifungal secondary metabolite phenazine-1-carboxamide (PCN) that inhibits growth of Fusarium oxysporum f. sp. radius lycopersici the causative agent of tomato foot and root rot. Our previous work unraveled a cascade of genes regulating the PCN biosynthesis operon, phzABCDEFGH. Via a genetic screen, we identify in this study a novel TetR/AcrR regulator, named Pip (phenazine inducing protein), which is essential for PCN biosynthesis. A combination of a phenotypical characterization of a pip mutant, in trans complementation assays of various mutant strains, and electrophoretic mobility shift assays identified Pip as the fifth DNA-binding protein so far involved in regulation of PCN biosynthesis. In this regulatory pathway, Pip is positioned downstream of PsrA (Pseudomonas sigma factor regulator) and the stationary-phase sigma factor RpoS, while it is upstream of the quorum-sensing system PhzI/PhzR. These findings provide further evidence that the path leading to the expression of secondary metabolism gene clusters in Pseudomonas species is highly complex.

| S-EPMC1698184 | biostudies-literature

The structural biology of phenazine biosynthesis.

Project description:The phenazines are a class of over 150 nitrogen-containing aromatic compounds of bacterial and archeal origin. Their redox properties not only explain their activity as broad-specificity antibiotics and virulence factors but also enable them to function as respiratory pigments, thus extending their importance to the primary metabolism of phenazine-producing species. Despite their discovery in the mid-19th century, the molecular mechanisms behind their biosynthesis have only been unraveled in the last decade. Here, we review the contribution of structural biology that has led to our current understanding of phenazine biosynthesis.

| S-EPMC4268259 | biostudies-literature

Phenazine antibiotic biosynthesis in Pseudomonas aureofaciens 30-84 is regulated by PhzR in response to cell density.

Project description:We have identified a gene that acts in trans to activate the expression of the phenazine biosynthetic genes in the biological control organism Pseudomonas aureofaciens 30-84. This gene, phzR (phenazine regulator), is located upstream of and divergently transcribed from the phenazine biosynthetic genes. Thus, the phenazine biosynthetic locus consists of at least two divergently transcribed operons. A functional phzR gene is required for phenazine production. The nucleotide sequence of phzR revealed an open reading frame of 723 nucleotides encoding a protein of ca. 27 kDa. The predicted amino acid sequence of PhzR has homology with other bacterial positive transcriptional activators, including LasR of Pseudomonas aeruginosa, LuxR of Vibrio fischerii, and TraR of Agrobacterium tumefaciens. The addition of cell-free supernatants from late-exponential-phase cultures of strain 30-84 resulted in expression of a genomic phzB:lacZ reporter strain at a lower cell density than normal, indicating the possible presence of an autoinducer. These results indicate that PhzR is a member of a two-component sensor-regulator family with known or predicted carboxy-terminal DNA-binding domains which regulates gene expression in response to environmental and cell density signals.

| S-EPMC205594 | biostudies-other

Expected Practice as a Novel Antibiotic Stewardship Intervention.

Project description:"Expected practice" is a recently described method to alter clinical behavior. We implemented an expected practice around short-course antibiotic therapy, which was associated with decreased antibiotic utilization for multiple bacterial infections. Thus, we describe this expected practice as a novel, simple, and inexpensive tool to enhance antibiotic stewardship.

| S-EPMC6324551 | biostudies-other

Mechanisms and Specificity of Phenazine Biosynthesis Protein PhzF.

Project description:Phenazines are bacterial virulence and survival factors with important roles in infectious disease. PhzF catalyzes a key reaction in their biosynthesis by isomerizing (2 S,3 S)-2,3-dihydro-3-hydroxy anthranilate (DHHA) in two steps, a [1,5]-hydrogen shift followed by tautomerization to an aminoketone. While the [1,5]-hydrogen shift requires the conserved glutamate E45, suggesting acid/base catalysis, it also shows hallmarks of a sigmatropic rearrangement, namely the suprafacial migration of a non-acidic proton. To discriminate these mechanistic alternatives, we employed enzyme kinetic measurements and computational methods. Quantum mechanics/molecular mechanics (QM/MM) calculations revealed that the activation barrier of a proton shuttle mechanism involving E45 is significantly lower than that of a sigmatropic [1,5]-hydrogen shift. QM/MM also predicted a large kinetic isotope effect, which was indeed observed with deuterated substrate. For the tautomerization, QM/MM calculations suggested involvement of E45 and an active site water molecule, explaining the observed stereochemistry. Because these findings imply that PhzF can act only on a limited substrate spectrum, we also investigated the turnover of DHHA derivatives, of which only O-methyl and O-ethyl DHHA were converted. Together, these data reveal how PhzF orchestrates a water-free with a water-dependent step. Its unique mechanism, specificity and essential role in phenazine biosynthesis may offer opportunities for inhibitor development.

| S-EPMC5524880 | biostudies-literature

Diversity and evolution of the phenazine biosynthesis pathway.

Project description:Phenazines are versatile secondary metabolites of bacterial origin that function in biological control of plant pathogens and contribute to the ecological fitness and pathogenicity of the producing strains. In this study, we employed a collection of 94 strains having various geographic, environmental, and clinical origins to study the distribution and evolution of phenazine genes in members of the genera Pseudomonas, Burkholderia, Pectobacterium, Brevibacterium, and Streptomyces. Our results confirmed the diversity of phenazine producers and revealed that most of them appear to be soil-dwelling and/or plant-associated species. Genome analyses and comparisons of phylogenies inferred from sequences of the key phenazine biosynthesis (phzF) and housekeeping (rrs, recA, rpoB, atpD, and gyrB) genes revealed that the evolution and dispersal of phenazine genes are driven by mechanisms ranging from conservation in Pseudomonas spp. to horizontal gene transfer in Burkholderia spp. and Pectobacterium spp. DNA extracted from cereal crop rhizospheres and screened for the presence of phzF contained sequences consistent with the presence of a diverse population of phenazine producers in commercial farm fields located in central Washington state, which provided the first evidence of United States soils enriched in indigenous phenazine-producing bacteria.

| S-EPMC2813009 | biostudies-literature

Selectively targeting bromodomain and extraterminal proteins for degradation as a novel anti-glioblastoma strategy [RNA-seq]

Project description:Purpose: Characterization of mechanism and vulnerability of BET protein dependency in GBM cells. Methods: ChIP-seq and RNA-seq were performed on GBM cells at different time points following treatment with dBET6, a novel BET protein degrader. The transcriptome responses of parental and JQ1-resistant U87 cells to JQ1 and dBET6 were compared as well. Result: This study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins by dBET6 in GBM.

2018-05-15 | GSE99175 | GEO

Selectively targeting bromodomain and extraterminal proteins for degradation as a novel anti-glioblastoma strategy [ChIP-seq]

2018-05-15 | GSE99171 | GEO

Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy.

Project description:MYCN-amplified (MNA) neuroblastoma is an aggressive neural crest-derived pediatric cancer. However, MYCN is indispensable for development and transcriptionally regulates extensive network of genes. Integrating anti-MYCN ChIP-seq and gene expression profiles of neuroblastoma patients revealed the metabolic enzymes, MTHFD2 and PAICS, required for one-carbon metabolism and purine biosynthesis were concomitantly upregulated, which were more susceptible to metastatic neuroblastoma. Moreover, we found that MYCN mediated the folate cycle via MTHFD2, which contributed one-carbon unit to enhance purine synthesis, and further regulated nucleotide production by PAICS in response to cancer progression. Dual knockdown of the MYCN-targeted gene pair, MTHFD2 and PAICS, in MNA neuroblastoma cells synergically reduced cell proliferation, colony formation, migration ability, and DNA synthesis. By systematically screening the compound perturbagens, the gene expression levels of MTHFD2 and PAICS were specifically suppressed by anisomycin and apicidin across cell lines, and our co-treatment results also displayed synergistic inhibition of MNA neuroblastoma cell proliferation. Collectively, targeting a combination of MYCN-targeted genes that interrupts the interconnection of metabolic pathways may overcome drug toxicity and improve the efficacy of current therapeutic agents in MNA neuroblastoma.

| S-EPMC6797810 | biostudies-literature

Novel fluorescent glycan microarray strategy reveals ligands for galectins.

Project description:Galectin-1 (Gal-1) and galectin-3 (Gal-3) are widely expressed galectins with immunoregulatory functions in animals. To explore their glycan specificity, we developed microarrays of naturally occurring glycans using a bifunctional fluorescent linker, 2-amino-N-(2-aminoethyl)-benzamide (AEAB), directly conjugated through its arylamine group by reductive amination to free glycans to form glycan-AEABs (GAEABs). Glycans from natural sources were used to prepare over 200 GAEABs, which were purified by multidimensional high-pressure liquid chromatography and covalently immobilized onto N-hydroxysuccinimide-activated glass slides via their free alkylamine. Fluorescence-based screening demonstrated that Gal-1 recognizes a wide variety of complex N-glycans, whereas Gal-3 primarily recognizes poly-N-acetyllactosamine-containing glycans independent of N-glycan presentation. GAEABs provide a general solution to glycan microarray preparation from natural sources for defining the specificity of glycan-binding proteins.

| S-EPMC2662446 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data