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

24 July 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


glmS riboswitch

Supplementary materials

Supporting Information
Assignment of diastereomers by Mosher ester analysis; determination of pKa values; synthesis and preparation of RNA; kinetic self-cleavage assay; general experimental methods; syntheses; NMR spectra


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.