| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 4360953 | Cell Host & Microbe | 2015 | 11 Pages |
•c-di-AMP is predicted to be essential in many pathogens and is thus an ideal PAMP•ΔdacA mutants lacking c-di-AMP contain suppressor mutations within a (p)ppGpp synthase•Decreased c-di-AMP increases (p)ppGpp, which inhibits growth via inactivation of CodY•In minimal medium, which favors CodY inactivation, dacA is no longer essential
SummaryCyclic di-adenosine monophosphate (c-di-AMP) is a widely distributed second messenger that appears to be essential in multiple bacterial species, including the Gram-positive facultative intracellular pathogen Listeria monocytogenes. In this study, the only L. monocytogenes diadenylate cyclase gene, dacA, was deleted using a Cre-lox system activated during infection of cultured macrophages. All ΔdacA strains recovered from infected cells harbored one or more suppressor mutations that allowed growth in the absence of c-di-AMP. Suppressor mutations in the synthase domain of the bi-functional (p)ppGpp synthase/hydrolase led to reduced (p)ppGpp levels. A genetic assay confirmed that dacA was essential in wild-type but not strains lacking all three (p)ppGpp synthases. Further genetic analysis suggested that c-di-AMP was essential because accumulated (p)ppGpp altered GTP concentrations, thereby inactivating the pleiotropic transcriptional regulator CodY. We propose that c-di-AMP is conditionally essential for metabolic changes that occur in growth in rich medium and host cells but not minimal medium.
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