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Switching to new anti-bacterial targets: Riboswitches
December 19, 2005New Haven, Conn. - The recently emerged field of bacterial riboswitches may be a good hunting ground for effective targets against bacterial infection, according to a report by Yale researchers in the journal Chemistry and Biology.
Riboswitches are RNA elements that control gene expression in essential metabolic pathways. Researchers in the laboratory of Ronald R. Breaker, the Henry Ford II Professor of Molecular, Cellular and Developmental Biology at Yale, showed that a riboswitch controlling vitamin B1 (thiamine) levels is disrupted in the presence of pyrithiamine, a toxic compound related to the vitamin.
Bacteria and fungi fail to grow in pyrithiamine and become resistant by acquiring mutations in their riboswitches. This work, in combination with the recently solved crystal structures of purine riboswitches, opens a path to the directed design of drugs targeting riboswitches for use as antibiotics.
According to the researchers, it is inevitable that bacteria will evolve and that the drugs we use to cure bacterial infections will eventually become ineffective. While it is often possible to alter existing drugs slightly, they suggest that a longer term and more attractive solution is to create entirely new drugs that target bacteria in completely new ways. This approach lengthens the useful clinical lifetime of a drug and makes it possible to tackle resistant 'superbugs' with combinations of drugs.
The analog, pyrithiamine, was synthesized decades ago to study the then new field of vitamin nutrition. It was quickly found to be toxic but the mechanism was incompletely understood. Breaker and coworkers show that pyrithiamine is metabolized and binds to the riboswitch controlling thiamine.
Co-authors at Yale on the work are Narasimhan Sudarsan, Smadar Cohen-Chalamish, Shingo Nakamura and Gail Mitchell Emilsson. The study was funded by the Defense Advanced Research Projects Agency, National Institutes of Health, and the David and Lucile Packard Foundation.
Breaker, a Howard Hughes Medical Institute Investigator, is co founder of BioRelix, a company pursuing licensing of intellectual property related to riboswitches.
Yale University
According to the researchers, it is inevitable that bacteria will evolve and that the drugs we use to cure bacterial infections will eventually become ineffective. While it is often possible to alter existing drugs slightly, they suggest that a longer term and more attractive solution is to create entirely new drugs that target bacteria in completely new ways. This approach lengthens the useful clinical lifetime of a drug and makes it possible to tackle resistant 'superbugs' with combinations of drugs.
The analog, pyrithiamine, was synthesized decades ago to study the then new field of vitamin nutrition. It was quickly found to be toxic but the mechanism was incompletely understood. Breaker and coworkers show that pyrithiamine is metabolized and binds to the riboswitch controlling thiamine.
Co-authors at Yale on the work are Narasimhan Sudarsan, Smadar Cohen-Chalamish, Shingo Nakamura and Gail Mitchell Emilsson. The study was funded by the Defense Advanced Research Projects Agency, National Institutes of Health, and the David and Lucile Packard Foundation.
Breaker, a Howard Hughes Medical Institute Investigator, is co founder of BioRelix, a company pursuing licensing of intellectual property related to riboswitches.
Yale University
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More Riboswitches Current Events and Riboswitches News Articles
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Riboswitches: Methods and Protocols (Methods in Molecular Biology) by Alexander Serganov (Editor) The revolutionary discoveries of RNA interference and bacterial regulatory RNAs led to further breakthroughs such as the identification of riboswitches and related RNA sensors, mRNA regions capable of alternating their conformations in response to the presence of cellular metabolites and other physical or chemical cues. In "Riboswitches: Methods and Protocols", expert researchers provide comprehensive and up-to-date coverage of various methods used to study riboswitches and other RNAs involved in gene expression control. Examining biochemical and modern biophysical techniques, the volume focuses on mRNAs responding to small organic molecules but expands the definition of a riboswitch to incorporate classes of RNA that undergo conformational transitions in response to other stimuli in... |
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Non-Protein Coding RNAs (Springer Series in Biophysics) by Nils G. Walter (Editor), Sarah A. Woodson (Editor), Robert T. Batey (Editor) This book assembles chapters from experts in the Biophysics of RNA to provide a broadly accessible snapshot of the current status of this rapidly expanding field. The 2006 Nobel Prize in Physiology or Medicine was awarded to the discoverers of RNA interference, highlighting just one example of a large number of non-protein coding RNAs. Because non-protein coding RNAs outnumber protein coding genes in mammals and other higher eukaryotes, it is now thought that the complexity of organisms is correlated with the fraction of their genome that encodes non-protein coding RNAs. Essential biological processes as diverse as cell differentiation, suppression of infecting viruses and parasitic transposons, higher-level organization of eukaryotic chromosomes, and gene expression itself are found to... |
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