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Novel TPP-riboswitch activators bypass metabolic enzyme dependency

Lünse, Christina E., Scott, Fraser J., Suckling, Colin J. and Mayer, Günter (2014) Novel TPP-riboswitch activators bypass metabolic enzyme dependency. Frontiers in Chemistry, 2. ISSN 2296-2646

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Abstract

Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have become increasingly interesting as promising antibacterial targets. Here, we describe thiamine analogs containing a central 1,2,3-triazole group to induce repression of thiM-riboswitch dependent gene expression in different E. coli strains. Additionally, we show that compound activation is dependent on proteins involved in the metabolic pathways of thiamine uptake and synthesis. The most promising molecule, triazolethiamine (TT), shows concentration dependent reporter gene repression that is dependent on the presence of thiamine kinase ThiK, whereas the effect of pyrithiamine (PT), a known TPP-riboswitch modulator, is ThiK independent. We further show that this dependence can be bypassed by triazolethiamine-derivatives that bear phosphate-mimicking moieties. As triazolethiamine reveals superior activity compared to pyrithiamine, it represents a very promising starting point for developing novel antibacterial compounds that target TPP-riboswitches. Riboswitch-targeting compounds engage diverse endogenous mechanisms to attain in vivo activity. These findings are of importance for the understanding of compounds that require metabolic activation to achieve effective riboswitch modulation and they enable the design of novel compound generations that are independent of endogenous activation mechanisms

Item Type: Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Schools: School of Applied Sciences
Depositing User: Fraser Scott
Date Deposited: 15 Aug 2017 09:48
Last Modified: 24 Sep 2017 00:10
URI: http://eprints.hud.ac.uk/id/eprint/32651

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