Genome-wide bioinformatics analysis of FMN, SAM-I, glmS, TPP, lysine, purine, cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria

Pavlova, Nikolet; Penchovsky, Robert

doi:10.1080/14728222.2019.1618274

Cited by 27 publications

(52 citation statements)

References 60 publications

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“…The glmS riboswitch is found in 920 bacterial species according to the Rfam 14.1 database. Among them are present 26 pathogenic bacteria responsible for various diseases and infections in humans . We provide an overview of all of them with the current antibiotics against them and resistance cases (Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…Among them are present 26 pathogenic bacteria responsible for various diseases and infections in humans. 22 We provide an overview of all of them with the current antibiotics against them and resistance cases (Table S1). There are 13 Gram-positive and 14 Gram-negative bacteria containing the glmS riboswitch.…”

Section: Analyses Of Biochemical Pathways For Syntheses Of Glcn6p And...mentioning

confidence: 99%

“…The article is an experimental continuation of two previous papers on bioinformatics analyses of bacterial riboswitches as antibacterial drug targets. 22,23 Here, we employ antisense oligonucleotides (ASOs) that bind specifically to a complementary region of the glmS riboswitch, located in the 5′-untranslated region (UTR) of bacterial mRNAs. 24−27 Riboswitches selectively bind to specific metabolites or metal ions, and as a result, go through conformational changes that alter the gene expression of essential proteins in bacterial metabolism.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This paper describes a novel approach to antibacterial drug development that uses bacterial riboswitches as targets for discovering new antibacterial drug candidates. The article is an experimental continuation of two previous papers on bioinformatics analyses of bacterial riboswitches as antibacterial drug targets. , Here, we employ antisense oligonucleotides (ASOs) that bind specifically to a complementary region of the glmS riboswitch, located in the 5′-untranslated region (UTR) of bacterial mRNAs. − …”

Section: Introductionmentioning

confidence: 99%

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Targeting glmS Ribozyme with Chimeric Antisense Oligonucleotides for Antibacterial Drug Development

2021

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Due to the steady rise of multidrug-resistant pathogenic bacteria worldwide, it is critical to develop novel antibacterial drugs. This article presents chimeric antisense oligonucleotides that inhibit the bacterial growth of Staphylococcus aureus, one of the most frequent causes of hospital-acquired infections. The chimeric antisense oligonucleotides have a combination of first- and second-generation chemical modification. To deliver the antisense oligonucleotides into a cell, we apply a cell-penetrating oligopeptide attached to them. We have performed complete bioinformatics analyses of the glmS ribozyme present in S. aureus and its essential role in the biochemical pathway of glucosamine-6-phosphate synthesis. Besides, we have analyzed the bacteria for alternative metabolic pathways, such as the nagA gene. The first antisense oligonucleotide explicitly targets the glmS riboswitch, while the second explicitly targets the nagA mRNA. We have evaluated that combined, the antisense oligonucleotides block the synthesis of glucosamine-6-phosphate entirely and inhibit the bacterial growth of S. aureus. However, the glmS riboswitch targeting the antisense oligonucleotide is sufficient to inhibit the growth of S. aureus with a MIC80 of 5 μg/mL. The glmS ribozyme is a very suitable target for antibacterial drug development with antisense oligonucleotides.

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Section: Resultsmentioning

confidence: 99%

Section: Analyses Of Biochemical Pathways For Syntheses Of Glcn6p And...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting glmS Ribozyme with Chimeric Antisense Oligonucleotides for Antibacterial Drug Development

2021

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“…On the basis of genome-wide bioinformatics analysis, it was suggested that several riboswitches are promising targets for antibacterial drug discovery. 4 Cobalamin (vitamin B12) riboswitch is a cisregulatory element widely found in the 5′-UTRs of the vitamin B12-associated genes in bacteria, resulting in modulation and production of a particular protein. A riboswitch generally consists of an aptamer and an expression platform.…”

Section: Introductionmentioning

confidence: 99%

Conformational Ensemble of TteAdoCbl Riboswitch Provides Stable Structural Elements for Conformation Selection and Population Shift in Cobalamin Recognition

Bai

Nussinov

et al. 2021

J. Phys. Chem. B

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Cobalamin riboswitch is a cis-regulatory element widely found in the 5′-UTRs of the vitamin B12-associated genes in bacteria, resulting in modulation and production of a particular protein. Thermoanaerobacter tengcongensis (Tte) AdoCbl riboswitches are the largest of the known riboswitches with 210 nucleotides, partially due to its long peripheral P6-extension, which enable high affinity of AdoCbl. Two structural elements, T-loop/T-looplike motif and kissing loop are key to the global folding of the RNA. While the structure of the TteAdoCbl riboswitch complex is known, we still do not understand the structure and conformation before AdoCbl ligand recognition. In order to delineate the conformational changes and the stabilities of long-range interactions, we have performed extensive all-atom replica-exchange molecular dynamics simulations of the TteAdoCbl riboswitch with a total simulation time of 2296 ns. We found that both the T-loop/T-looplike motif and kissing loop are very stable with ligand binding. The gating conformation changes of P6-extension allow the ligand to bind to the preorganized kissing loop binding pocket. The T-loop/T-looplike motif has much more hydrogen bonds than observed in TteAdoCbl riboswitch complex crystal structure, indicating an allosteric response of the T-loop/T-looplike motif. Our study demonstrated that the conformational ensemble of TteAdoCbl riboswitch provides stable structural elements for conformation selection and population shift in cobalamin recognition.

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Multidimensional Applications and Challenges of Riboswitches in Biosensing and Biotherapy

Wu,

Zhu,

Zhang

et al. 2023

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Riboswitches have received significant attention over the last two decades for their multiple functionalities and great potential for applications in various fields. This article highlights and reviews the recent advances in biosensing and biotherapy. These fields involve a wide range of applications, such as food safety detection, environmental monitoring, metabolic engineering, live cell imaging, wearable biosensors, antibacterial drug targets, and gene therapy. The discovery, origin, and optimization of riboswitches are summarized to help readers better understand their multidimensional applications. Finally, this review discusses the multidimensional challenges and development of riboswitches in order to further expand their potential for novel applications.

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Genome-wide bioinformatics analysis of FMN, SAM-I, glmS, TPP, lysine, purine, cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria

Cited by 27 publications

References 60 publications

Targeting glmS Ribozyme with Chimeric Antisense Oligonucleotides for Antibacterial Drug Development

Targeting glmS Ribozyme with Chimeric Antisense Oligonucleotides for Antibacterial Drug Development

Conformational Ensemble of TteAdoCbl Riboswitch Provides Stable Structural Elements for Conformation Selection and Population Shift in Cobalamin Recognition

Multidimensional Applications and Challenges of Riboswitches in Biosensing and Biotherapy

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