To survive extreme and rapidly changing conditions, bacteria sense environmental changes and then respond with appropriate alterations in gene expression and protein activity. Bacterial adaptation to environmental signals plays important roles in human health, including how bacteria respond to anti-bacterial treatments and how bacteria switch from free-living to invading a host. Therefore, an important scientific challenge is to identify mechanisms that allow bacteria to sense external cues and translate those cues into internal signals that maximize survival. Novel intracellular small molecule signals, 2’, 3’-cyclic nucleotide monophosphates (2’, 3’-cNMPs), have been recently discovered in eukaryotes and prokaryotes. Within plants and mammals, wounding has been found to cause increased levels of 2’, 3’-cNMPs, suggesting an intriguing connection between 2’,3’-cNMPs and cellular stress. 2’, 3’-cNMP levels in E. coli are generated specifically from RNase I-catalyzed RNA degradation and RNase I. Studies in bacteria have demonstrated that 2′,3′-cNMP levels affect bacterial phenotypes, such as biofilm formation, motility, and growth, and modulate expression of numerous genes, suggesting that 2′,3′-cNMP levels are monitored by cells. With the aim to develop a mechanistic understanding of 2’,3’-cNMP signaling, 2’,3’-cNMP based resins have been synthesized and used as a bait in affinity-based chromatography to capture the proteins and validate their role in signal transduction. The pull-down experiments have revealed abundant ribosomal proteins among several other protein hits which drew our attention towards investigating the role of 2’,3’-cNMP in the “central dogma” of bacterial cells. Using <i>in vitro</i> translation assays, we have demonstrated that 2′,3′-cNMPs inhibit translation at concentrations found in amino acid-starved cells. In addition, a genetically encoded tool to increase cellular 2′,3′-cNMP levels was developed and was demonstrated to decrease <i>E. coli</i> growth rates. Overall, our research suggests a mechanism for 2′,3-cNMP levels to modulate bacterial phenotypes by rapidly affecting translation.

Binding of 2’,3’-cyclic nucleotide monophosphates to bacterial ribosomes inhibits translation

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