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Discovery and characterization of the antimetabolite action of thioacetamide-linked 1,2,3-triazoles as disruptors of cysteine biosynthesis in Gram-negative bacteria

ABSTRACT: Discovery and characterization of the antimetabolite action of thioacetamide-linked 1,2,3-triazoles as disruptors of cysteine biosynthesis in Gram-negative bacteria

PROVIDER: PRJNA596200 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10719769_1.fastq.gz	Fastqsanger.gz
	SRR10719769_2.fastq.gz	Fastqsanger.gz
	SRR10719770_1.fastq.gz	Fastqsanger.gz
	SRR10719770_2.fastq.gz	Fastqsanger.gz
	SRR10719771_1.fastq.gz	Fastqsanger.gz

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Discovery and characterization of the antimetabolite action of thioacetamide-linked 1,2,3-triazoles as disruptors of cysteine biosynthesis in Gram-negative bacteria

Project description:Increasing rates of drug-resistant Gram-negative (GN) infections combined with a lack of new GN-effective antibiotic classes is driving the need for the discovery of new agents. As bacterial metabolism represents an underutilized mechanism targeted in current antimicrobial therapies, we sought to identify novel antimetabolites and explore the specific impacts of these inhibitors on key pathways in bacterial metabolism. This study describes the successful application of this approach to discover N-(phenyl) thioacetamide-linked 1,2,3-triazoles (TAT) that target cysteine synthase A (CysK), an enzyme unique to bacteria that is positioned at a key juncture between several fundamental pathways. The TAT class was identified using a high-throughput screen against Escherichia coli designed to identify modulators of pathways related to folate biosynthesis. TAT analog synthesis revealed a clear structure-activity relationship, and activity was confirmed against GN antifolate-resistant clinical isolates. Spontaneous TAT resistance mutations were tracked to CysK, and mode of action studies led to the identification of a false product formation mechanism between the CysK substrate O-acetyl-L-serine and the TATs. Global transcriptional responses to TAT treatment revealed that these antimetabolites impose substantial disruption of key metabolic networks beyond cysteine biosynthesis. This study highlights the potential of antimetabolite drug discovery as a promising approach to the discovery of novel GN antibiotics.

2020-01-01 | GSE142164 | GEO

Discovery and Characterization of the Antimetabolite Action of Thioacetamide-Linked 1,2,3-Triazoles as Disruptors of Cysteine Biosynthesis in Gram-Negative Bacteria.

Project description:Increasing rates of drug-resistant Gram-negative (GN) infections, combined with a lack of new GN-effective antibiotic classes, are driving the need for the discovery of new agents. Bacterial metabolism represents an underutilized mechanism of action in current antimicrobial therapies. Therefore, we sought to identify novel antimetabolites that disrupt key metabolic pathways and explore the specific impacts of these agents on bacterial metabolism. This study describes the successful application of this approach to discover a new series of chemical probes, N-(phenyl)thioacetamide-linked 1,2,3-triazoles (TAT), that target cysteine synthase A (CysK), an enzyme unique to bacteria that is positioned at a key juncture between several fundamental pathways. The TAT class was identified using a high-throughput screen against Escherichia coli designed to identify modulators of pathways related to folate biosynthesis. TAT analog synthesis demonstrated a clear structure-activity relationship, and activity was confirmed against GN antifolate-resistant clinical isolates. Spontaneous TAT resistance mutations were tracked to CysK, and mode of action studies led to the identification of a false product formation mechanism between the CysK substrate O-acetyl-l-serine and the TATs. Global transcriptional responses to TAT treatment revealed that these antimetabolites impose substantial disruption of key metabolic networks beyond cysteine biosynthesis. This study highlights the potential of antimetabolite drug discovery as a promising approach to the discovery of novel GN antibiotics and the pharmacological promise of TAT CysK probes.

| S-EPMC7477787 | biostudies-literature

The identification of putative circulating miRNA biomarkers of Thioacetamide-induced hepatotoxicity.

Project description:The Thioacetamide-treated rat was first identified as a model of hepatotoxicity by Gupta in 1956 and is now well-established, not least because the histopathogical output closely mimics that seen in humans with chronic liver disease. Acute treatment of rats with Thioacetamide causes pronounced necrosis and inflammation. Animals received intraperitoneal (ip) doses of vehicle-only (0.9% (v/v) saline) (n=3), or 100 mg/kg Thioacetamide (n=3) and were sacrificed after 24 hours. Blood was withdrawn via the descending vena cava and immediately transferred into potassium/EDTA tubes. Following centrifugation (16,100g, 4M-BM-0C, 5 min) the plasma was collected and stored at -80M-BM-0C. miRNA microarray profiling of RNA extracted from the plasma of rats treated with Thioacetamide revealed that a subset of miRNAs were differentially expressed following treatment. These miRNAs appeared to mediate pathways involved in hepatic fibrosis and stellate cell activation, suggesting that they might function as predictive biomarkers following compound-induced hepatotoxicity. The changes correlated well with increases in ALT levels, which are the current gold standard method for determining the extent of liver injury. Furthermore, it is hypothesised that particular aetiologies of liver damage might cause differing expression profiles of miRNAs, thus certain miRNAs could be implemented in a panel-type expression study to distinguish between different types of hepatic injury. Single channel miRNA microarrays were performed on n= 3 samples, 2 treatment groups; control and test. Control animals received vehicle-only (0.9% (v/v) saline) via the ip route. Test animals received 100 mg/kg Thioacetamide dissolved in 0.9% (v/v) saline, via the ip route. 24 h after dosing animals were sacrificed using decapitation under terminal anaesthesia.

2014-03-14 | E-GEOD-55885 | biostudies-arrayexpress

Critically ill patients with either gram-positive sepsis or gram-negative sepsis

Project description:Objective: It is unclear whether the host response of gram-positive sepsis differs from gram-negative sepsis at a transcriptome level. Using microarray technology, we compared the gene-expression profiles of gram-positive sepsis and gram-negative sepsis in critically ill patients. Design: A prospective cross-sectional study. Setting: A 20-bed general intensive care unit of a tertiary referral hospital. Patients: Seventy-two patients admitted to the intensive care unit. Interventions: Intravenous blood was collected for leukocyte separation and RNA extraction. Microarray experiements were then performed examing the expression level of 19,232 genes in each sample. Measurements and Main Results: There was no difference in the expression profile between gram-positive and gram-negative sepsis. The finding remained unchanged even when genes with lower expression level were included or after statistical stringency was lowered. There were, however, ninety-four genes differentially expressed between sepsis and control patients. These genes included those involved in immune regulation, inflammation and mitochondrial function. Hierarchical cluster analysis confirmed that the difference in gene expression profile existed between sepsis and control patients, but not between gram-positive and gram-negative patients. Conclusion: Gram-positive and gram-negative sepsis share a common host response at a transcriptome level. These findings support the hypothesis that the septic response is non-specific and is designed to provide a more general response that can be elicited by a wide range of different micro-organisms. Keywords: disease state analysis, gram-positive sepsis, gram-negative sepsis

2007-12-01 | GSE6535 | GEO

In vivo transcriptomic responses to thioacetamide exposure in guinea pig liver tissue

Project description:In this study we tested the ability to predict organ injury from transcriptomic data in Hartley guinea pigs at early time points after exposure to thioacetamide (9 and 33 hours). We selected thioacetamide, a compound extensively used in animal studies for its ability to cause liver damage.

2021-03-25 | GSE169545 | GEO

Probing liver injury induced by thioacetamide in human in vitro pooled hepatocyte experiments

Project description:In this study we tested the ability to predict liver injury from in vitro human pooled hepatocyte data after exposure to thioacetamide (24 hour). We selected thioacetamide, a compound extensively used in various studies for its ability to cause liver injury.

2024-04-03 | GSE250139 | GEO

A time-course study of thioacetamide (TAA)-induced liver fibrosis in rats

Project description:The aim is to characterize rat liver fibrosis induced by thioacetamide (TAA). To induce hepatic fibrosis, Male Sprague Dawley rats (9-12 weeks of age and 380-420 g of weight upon arrival, supplied by Beijing Vital River laboratory animal Co., Ltd.) were treated with thioacetamide (TAA). Rat liver samples were collected from five groups of rats at week 1, 2, 4, 8 and 13 after TAA (300 mg/kg) administration three times per week while five control groups receive the same volume of 0.9% normal saline. Four biological replicates were used for each group.

2021-09-29 | E-MTAB-10547 | biostudies-arrayexpress

Conserved Spermatogonial Gene Networks Couple to Glutathione and Pentose Phosphate Metabolism but not Cysteine Biosynthesis

Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.

2020-12-17 | GSE163302 | GEO

In vitro transcriptomic responses to thioacetamide-S-oxide exposure in human primary hepatocytes, renal tube epithelial, and cardiomyocytes

Project description:In this study we tested the ability to predict organ injury endpoints from in vitro transcriptomics responses at early time points (9 and 24 hours) after to thioacetamide-S-oxide treatment, the toxic metabolite of thioacetamide. Thioacetamide, an organosulfur compound, have been extensively used in animal studies as a hepatotoxin and carcinogen for its ability to cause acute liver damage.

2020-06-03 | GSE134641 | GEO

Expression profiles of liver tissues from wild-type and AID transgenic mice exposed to thioacetamide hepatotoxicity

Project description:AID is an intrinsic DNA mutator enzyme and contributes to tumorigenesis through the accumulation of genetic aberrations. To examine whether mutagenesis induced by AID during inflammation-associated hepatocarcinogenesis depends on the transcriptional levels of the target genes, we performed the gene expression profiling of liver tissues from AID transgenic mice and wild-type mice with and without thioacetamide treatment. AID transgenic mice and wild-type mice were administered with thioacetamide in drinking water for 6 months, and the gene expression levels of their livers are compared.

2015-07-10 | E-GEOD-62878 | biostudies-arrayexpress

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