Antibiotic Development by Investigation of the glmS Riboswitch

Abstract

Although bacterial infections have always been of significant interest to researchers and physicians, the drug-resistant bacterial strains that have recently developed are causing new concerns and are much more difficult to combat. Our current methods for treating bacterial infections include broad-spectrum antibiotics which target only a small number of bacterial processes. However, with the discovery of riboswitches, we are developing new ways to fight bacterial infections which make use of their own natural metabolic pathways, essentially causing bacteria to destroy themselves. Riboswitches are found in non-coding regions of messenger RNAs and these RNA elements bind to ligands to control the expression of nearby genes. The glucosamine-6-phosphate (glmS) riboswitch is unique in that upon binding its ligand, glucosamine-6-phosphate (GlcN6P), it undergoes self-cleavage and is therefore also a catalytic RNA. The cleavage event targets the RNA for subsequent degradation, thereby repressing further gene expression. To study the glmS riboswitch, initial experiments were performed to determine the mechanism followed upon binding of the natural ligand. Since then, analogs of the natural ligand have been obtained and are being tested for their catalytic capabilities through kinetic analyses and rate constant calculations. Once successful candidates have been determined, these non-natural ligands will be introduced into live bacterial cultures, hopefully disrupting normal cell metabolism and reproduction. If successful, these analogs could be used as novel antibiotics, offering a more specific mode of targeting a wide variety of bacterial species.