Phosphonate and Thia-Sugar Analogs of Glucosamine-6-phosphate: Activation of the glmS Riboswitch

The glmS riboswitch is a motif found in 5’-untranslated regions of bacterial mRNA that controls the synthesis of glucosamine-6-phosphate (GlcN6P), an essential building block for the bacterial cell wall, by a feed-back mechanism. Activation of the glmS riboswitch by GlcN6P mimics interferes with the bacterial ability to synthesize its cell wall. Accordingly, GlcN6P mimics acting as glmS activators are promising candidates for future antibiotic drugs that may overcome emerging bacterial resistance against established antibiotics. We describe the synthesis of a series of phosphonate mimics of GlcN6P as well as the thia-sugar analogue of GlcN6P. The phosphonate mimics differ in their pKa value to answer the question whether derivatives with a pKa matching that of GlcN6P would be efficient glmS activators. We found that all derivatives activate the riboswitch, however, less efficiently than GlcN6P. This observation can be explained by missing hydrogen bonds in the case of phosphonates and is a valuable information for the design of future GlcN6P mimics. The thia-sugar analogue of GlcN6P on the other hand turned out to be a glmS riboswitch activator with the same activity as the natural metabolite GlcN6P. Therefore, the compound is a promising lead structure for the development of future antibiotics with a novel mode of action.