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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.

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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.

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