Switching to New Anti-Bacterial Targets: Riboswitches
|Early studies to understand the malnutrition disease, beri beri, led to the identification of vitamin B1 (thiamine, inset, top), a nutrient found in brown rice but not polished white rice. The thiamine analog pyrithiamine (inset, bottom) has toxic effects in bacteria, fungi, and mammals — now shown to be caused in part by interactions with thiamine-specific riboswitches. Upper image is Aspergillus oryzae, a fungus that contains the riboswitch and is killed by pyrithiamine.
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.
Citation: Chemistry and Biology : (December 19, 2005)