Carba-sugars Activate the glmS-Riboswitch of <i>Staphylococcus aureus</i>

Lünse, Christina E.; Schmidt, Magnus S.; Wittmann, Valentin; Mayer, Günter

doi:10.1021/cb200016d

Cited by 69 publications

(113 citation statements)

References 32 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…Similarly, our observation that a number of distinct azaaromatic compounds activate gene expression cannot be used as confirmation that the natural ligand or ligands for this riboswitch class can be classified as azaaromatic. It is possible to design and synthesize compounds that trick riboswitches into regulating gene expression by binding the natural ligand-binding pocket (Blount et al 2007(Blount et al , 2015Kim et al 2009;Mulhbacher et al 2010;Lünse et al 2011;Howe et al 2015). Therefore, the azaaromatic compounds that trigger gene expression in the current study might only be distal mimics of the natural target.…”

Section: Discussionmentioning

confidence: 99%

“…We are unable to formulate a compelling structural model for the precise natural ligand by using the SAR data derived from our binding and gene expression assays and by using the SAR data derived from both the hits and the inactive compounds in the Biolog Phenotype MicroArray assay. Previous efforts with other riboswitch classes have successfully identified drug-like compounds that are bound nearly as tightly by the riboswitch as its natural ligand (Blount et al 2007(Blount et al , 2015Kim et al 2009;Mulhbacher et al 2010;Lünse et al 2011). Although each of these compounds is a relatively close analog of the natural ligand, the yjdF motif RNAs examined in the current study bind to a large diversity of azaaromatic compounds.…”

Section: The Natural Ligand For Azaaromatic Riboswitches Remains Unknownmentioning

confidence: 95%

See 1 more Smart Citation

The yjdF riboswitch candidate regulates gene expression by binding diverse azaaromatic compounds

Hwang

Stav

et al. 2016

RNA

View full text Add to dashboard Cite

The yjdF motif RNA is an orphan riboswitch candidate that almost exclusively associates with the yjdF protein-coding gene in many bacteria. The function of the YjdF protein is unknown, which has made speculation regarding the natural ligand for this putative riboswitch unusually challenging. By using a structure-probing assay for ligand binding, we found that a surprisingly broad diversity of nitrogen-containing aromatic heterocycles, or "azaaromatics," trigger near-identical changes in the structures adopted by representative yjdF motif RNAs. Regions of the RNA that undergo ligand-induced structural modulation reside primarily in portions of the putative aptamer region that are highly conserved in nucleotide sequence, as is typical for riboswitches. Some azaaromatic molecules are bound by the RNA with nanomolar dissociation constants, and a subset of these ligands activate riboswitch-mediated gene expression in cells. Furthermore, genetic elements most commonly adjacent to the yjdF motif RNA or to the yjdF protein-coding region are homologous to protein regulators implicated in mitigating the toxic effects of diverse phenolic acids or polycyclic compounds. Although the precise type of natural ligand sensed by yjdF motif RNAs remains unknown, our findings suggest that this riboswitch class might serve as part of a genetic response system to toxic or signaling compounds with chemical structures similar to azaaromatics.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: The Natural Ligand For Azaaromatic Riboswitches Remains Unknownmentioning

confidence: 95%

The yjdF riboswitch candidate regulates gene expression by binding diverse azaaromatic compounds

Hwang

Stav

et al. 2016

RNA

View full text Add to dashboard Cite

show abstract

“…39 Ligand affinity differs not only between distinct riboswitch classes but also within riboswitches of one class. For example, GlcN6P activates the glmS riboswitch of S. aureus with a determined half-maximal effective concentration (EC 50 value) of ∼4 μM, 40 whereas the homologous representative from B. subtilis is activated at 50-fold higher metabolite concentrations (EC 50 ≈ 200 μM). 27 This observation of varying affinities for the same ligand in the same riboswitch class is supported by the identification of a tunable aptamer region in the purine riboswitch.…”

Section: ■ Ligand Binding and Rna Switchingmentioning

confidence: 99%

“…This has been realized in the case of the self-cleaving glmS riboswitch, which is even adaptable to state-of-the-art high-throughput screening formats. 40,46 The riboswitches' strict discrimination between closely related molecules through multiple interactions and ligandencircling binding pockets make artificial ligand identification a challenging task. Thus, design and testing of metabolite analogues are limited by a small scope that allows incorporation of variations at different positions of the natural ligand without loss of binding.…”

Section: ■ Ligand Binding and Rna Switchingmentioning

confidence: 99%

(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

Matzner

Mayer

2015

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

The rise of antimicrobial resistance in human pathogenic bacteria has increased the necessity for the discovery of novel, yet unexplored antibacterial drug targets. Riboswitches, which are embedded in untranslated regions of bacterial messenger RNA (mRNA), represent such an interesting target structure. These RNA elements regulate gene expression upon binding to natural metabolites, second messengers, and inorganic ions, such as fluoride with high affinity and in a highly discriminative manner. Recently, efforts have been directed toward the identification of artificial riboswitch activators by establishing high-throughput screening assays, fragment-based screening, and structure-guided ligand design approaches. Emphasis in this review is placed on the special requirements and synthesis of new potential antibiotic drugs that target riboswitches in which dissimilarity is an important aspect in the design of potential lead compounds.

show abstract

“…Three of these riboswitch classes have been revealed as important cellular targets of antibacterial small molecules whose mechanism of action had not been previously defined (9)(10)(11)(12)(13). More recently, several publications have demonstrated that novel small molecules that bind to selected riboswitch aptamers with affinities comparable to that of the cognate ligand can be rationally identified and optimized (14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora

Blount

Megyola

Plummer

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Despite nearly 85 years of successful antibacterial chemotherapy, bacterial infections still pose a serious threat to human health. Continually emerging drug-resistant bacteria make existing agents less effective, and a paucity of new agents and decreased development effort from the pharmaceutical industry provide little hope of replenishing the arsenal (1, 2). Complications and mortality due to bacterial infections continue to increase, already reaching epidemic proportions in some areas of the world. If humans are to regain the upper hand in fighting bacterial infections, then innovation, investment, and new antibacterial agents will be needed. Although some of the barriers to the discovery and approval of new compounds are economic or policy related, there is also a desperate need for new targets and new mechanisms of action. A renewed effort to expand our knowledge of bacterial physiology and to translate discoveries into the clinic will be needed to address these challenges and to reinvigorate antibiotic development pipelines.Recent advances in our understanding of how bacteria maintain physiological homeostasis revealed a promising class of potential antibiotic targets called riboswitches-noncoding mRNAs that form a structured receptor (or aptamer) which can directly bind to a specific small-molecule ligand or ion and thereby regulate gene expression (3-5). Ligand binding to a riboswitch aptamer stabilizes a conformationally distinct architecture in the mRNA that modulates the expression of the adjacent coding region(s) (4-8). To date, more than 35 riboswitch classes have been discovered and characterized (7). Three of these riboswitch classes have been revealed as important cellular targets of antibacterial small molecules whose mechanism of action had not been previously defined (9-13). More recently, several publications have demonstrated that novel small molecules that bind to selected riboswitch aptamers with affinities comparable to that of the cognate ligand can be rationally identified and optimized (14-21).In some cases, synthetic or natural riboswitch ligand analogs have demonstrated potent antibacterial activity (12-15, 20, 22). For example, the phosphorylated form of roseoflavin (RoF) (

show abstract

Carba-sugars Activate the glmS-Riboswitch of Staphylococcus aureus

Cited by 69 publications

References 32 publications

The yjdF riboswitch candidate regulates gene expression by binding diverse azaaromatic compounds

The yjdF riboswitch candidate regulates gene expression by binding diverse azaaromatic compounds

(Dis)similar Analogues of Riboswitch Metabolites as Antibacterial Lead Compounds

Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora

Contact Info

Product

Resources

About