The promise of riboswitches as potential antibacterial drug targets

Lünse, Christina E.; Schüller, Anna; Mayer, Günter

doi:10.1016/j.ijmm.2013.09.002

Cited by 65 publications

(60 citation statements)

References 117 publications

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“…Riboswitches in particular are being pursued as antibiotic targets due to remarkable specificity and high affinity for their ligands (Lünse et al, 2014). At this point, one compound targeting the guanine riboswitch of S. aureus has been shown to successfully reduce bacterial concentrations in animals after infection (Ster et al, 2013).…”

Section: Small Rnas In Pathogenesis: From Discovery To Targetingmentioning

confidence: 99%

Small RNAs in mycobacteria: an unfolding story

Haning

Cho

Contreras

2014

Front. Cell. Infect. Microbiol.

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Mycobacteria represent a class of powerful pathogens, including those causing tuberculosis and leprosy, which continue to be worldwide health challenges. In the last 20 years, an abundance of non-coding, small RNAs (sRNAs) have been discovered in model bacteria and gained significant attention as regulators of cellular responses, including pathogenesis. Naturally, a search in mycobacteria followed, revealing over 200 sRNAs thus far. Characterization of these sRNAs is only beginning, but differential expression under environmental stresses suggests relevance to mycobacterial pathogenesis. This review provides a comprehensive overview of the current knowledge of sRNAs in mycobacteria, including historical perspective and techniques used for identification and characterization.

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Section: Small Rnas In Pathogenesis: From Discovery To Targetingmentioning

confidence: 99%

Small RNAs in mycobacteria: an unfolding story

Haning

Cho

Contreras

2014

Front. Cell. Infect. Microbiol.

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“…Artificial compounds acting successfully on riboswitches have to meet at least two criteria: (i) they must specifically bind to the relevant RNA structure and (ii) induce the conformational changes that finally lead to down- or up-regulation of gene expression. In recent years synthetic molecules that meet these criteria have been discovered for several riboswitch classes (Lünse et al, 2014). One of them is the TPP-riboswitch (Miranda-Rios et al, 2001; Winkler et al, 2002), which selectively interacts with thiamine pyrophosphate (TPP) by binding to its pyrimidine moiety through the so-called pyrimidine sensor helix (P2, J2-3, P3) of the aptamer domain.…”

Section: Introductionmentioning

confidence: 99%

Novel TPP-riboswitch activators bypass metabolic enzyme dependency

et al. 2014

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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.

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“…Small molecules that are structurally dissimilar to the natural ligand but which mimic its activity to selectively downregulate riboswitchcontrolled biosynthetic genes essential for growth (herein referred to as a synthetic mimic) could serve as mechanistically novel therapeutic agents [7][8][9][10][11][12] . Riboflavin (vitamin B 2 ) biosynthesis serves as one potentially attractive metabolic pathway to apply this strategy in antibacterial discovery [11][12][13][14] .…”

mentioning

confidence: 99%

“…Therefore, disrupting riboflavin biosynthesis either by synthetic mimics of FMN or enzyme inhibitors of the pathway represents a novel target for antibacterial intervention with limited predicted off-target effects. To date, little success has been achieved in identifying synthetic mimics of riboswitch ligands despite using a variety of in vitro screening strategies, including affinity-based or fragment-based screening, or structure-guided design approaches starting with natural ligands [7][8][9] . One of the best-characterized antimetabolite inhibitors to a riboswitch is roseoflavin 17 , a naturally-produced analogue of riboflavin, which targets FMN riboswitches from multiple bacterial species 11,13,18,19 .…”

mentioning

confidence: 99%

Selective small-molecule inhibition of an RNA structural element

Howe

Wang

Fischmann

et al. 2015

Nature

349

397

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Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

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The promise of riboswitches as potential antibacterial drug targets

Cited by 65 publications

References 117 publications

Small RNAs in mycobacteria: an unfolding story

Small RNAs in mycobacteria: an unfolding story

Novel TPP-riboswitch activators bypass metabolic enzyme dependency

Selective small-molecule inhibition of an RNA structural element

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