2019
DOI: 10.1371/journal.ppat.1007537
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Inhibition of the Staphylococcus aureus c-di-AMP cyclase DacA by direct interaction with the phosphoglucosamine mutase GlmM

Abstract: c-di-AMP is an important second messenger molecule that plays a pivotal role in regulating fundamental cellular processes, including osmotic and cell wall homeostasis in many Gram-positive organisms. In the opportunistic human pathogen Staphylococcus aureus, c-di-AMP is produced by the membrane-anchored DacA enzyme. Inactivation of this enzyme leads to a growth arrest under standard laboratory growth conditions and a re-sensitization of methicillin-resistant S. aureus (MRSA) strains to ß-lactam antibiotics. Th… Show more

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Cited by 49 publications
(116 citation statements)
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References 62 publications
(112 reference statements)
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“…This conclusion is based on our observation that the cellular c‐di‐AMP levels are also decreased in a gdpP mutant strain upon addition of glutamine or ammonium (Figure a). Current evidence suggests that the activity of DacA can be regulated through the interaction with two proteins: the membrane anchored and proposed DacA regulator protein YbbR (also named as CdaR in other bacteria) and the phosphoglucosamine mutase enzyme GlmM (Gundlach et al, ; Pham, Liang, Marcellin, & Turner, ; Tosi et al, ; Zhu et al, ). We could exclude that the observed reduction in cellular c‐di‐AMP levels in the presence of ammonium or glutamine is mediated by YbbR, as a ybbR mutant showed a similar decrease in the c‐di‐AMP levels as observed for the WT strain (Figure b).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…This conclusion is based on our observation that the cellular c‐di‐AMP levels are also decreased in a gdpP mutant strain upon addition of glutamine or ammonium (Figure a). Current evidence suggests that the activity of DacA can be regulated through the interaction with two proteins: the membrane anchored and proposed DacA regulator protein YbbR (also named as CdaR in other bacteria) and the phosphoglucosamine mutase enzyme GlmM (Gundlach et al, ; Pham, Liang, Marcellin, & Turner, ; Tosi et al, ; Zhu et al, ). We could exclude that the observed reduction in cellular c‐di‐AMP levels in the presence of ammonium or glutamine is mediated by YbbR, as a ybbR mutant showed a similar decrease in the c‐di‐AMP levels as observed for the WT strain (Figure b).…”
Section: Discussionmentioning
confidence: 99%
“…We could exclude that the observed reduction in cellular c‐di‐AMP levels in the presence of ammonium or glutamine is mediated by YbbR, as a ybbR mutant showed a similar decrease in the c‐di‐AMP levels as observed for the WT strain (Figure b). GlmM has been shown to be a negative regulator of DacA activity both in vivo and in vitro (Pham et al, ; Tosi et al, ) . However, since GlmM is likely an essential enzyme in S. aureus , we were unable to construct a glmM mutant and test its involvement in the observed repression of c‐di‐AMP synthesis in the presence of ammonium or glutamine as we did for the gdpP and ybbR mutant strains.…”
Section: Discussionmentioning
confidence: 99%
“…Recently, CdaA from S. aureus was characterized structurally and biochemically (24). Surprisingly, in contrast to L. monocytogenes CdaA, the S. aureus CdaA homolog shows activity not only in the presence of transition metal ions but also in the presence of Mg 2ϩ .…”
Section: Structures Of the Diadenylate Cyclase Cdaamentioning
confidence: 99%
“…7A). Current evidence suggests that the activity of DacA can be regulated through the interaction with two proteins: the membrane anchored regulator protein YbbR (also name CdaR in other bacteria) and the phosphoglucomutase enzyme GlmM (Tosi et al ., 2019, Zhu et al ., 2016, Gundlach et al ., 2015b, Pham et al ., 2016) (see Model Fig. 8).…”
Section: Discussionmentioning
confidence: 99%
“…GlmM converts glucosamine-6-P to glucosamine-1-P, an essential precursor for UDP-GlcNAc production and hence peptidoglycan synthesis. GlmM can block the c-di-AMP cyclase activity of DacA through a direct interaction (Tosi et al ., 2019, Zhu et al ., 2016). Glutamine is a key precursor for the production of the GlmM substrate glucosamine-6-P since it and fructose-6-P are converted by GlmS to glutamate and glucosamine-6-P.…”
Section: Discussionmentioning
confidence: 99%