Dataset Information

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B Streptococcus.

ABSTRACT: Streptococcus agalactiae is among the few pathogens that have not developed resistance to ß-lactam antibiotics despite decades of clinical use. The molecular basis of this long-lasting susceptibility has not been investigated, and it is not known whether specific mechanisms constrain the emergence of resistance. In this study, we first report ß-lactam tolerance due to the inactivation of the c-di-AMP phosphodiesterase GdpP. Mechanistically, tolerance depends on antagonistic regulation by the repressor BusR, which is activated by c-di-AMP and negatively regulates ß-lactam susceptibility through the BusAB osmolyte transporter and the AmaP/Asp23/GlsB cell envelope stress complex. The BusR transcriptional response is synergistic with the simultaneous allosteric inhibition of potassium and osmolyte transporters by c-di-AMP, which individually contribute to low-level ß-lactam tolerance. Genome-wide transposon mutagenesis confirms the role of GdpP and highlights functional interactions between a lysozyme-like hydrolase, the KhpAB RNA chaperone and the protein S immunomodulator in the response of GBS to ß-lactam. Overall, we demonstrate that c-di-AMP acts as a turgor pressure rheostat, coordinating an integrated response at the transcriptional and post-translational levels to cell wall weakening caused by ß-lactam activity, and reveal additional mechanisms that could foster resistance.

SUBMITTER: Brissac T

PROVIDER: S-EPMC11238645 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B <i>Streptococcus</i>.

Brissac Terry T Guyonnet Cécile C Sadouni Aymane A Hernández-Montoya Ariadna A Jacquemet Elise E Legendre Rachel R Sismeiro Odile O Trieu-Cuot Patrick P Lanotte Philippe P Tazi Asmaa A Firon Arnaud A

microLife 20240612

<i>Streptococcus agalactiae</i> is among the few pathogens that have not developed resistance to ß-lactam antibiotics despite decades of clinical use. The molecular basis of this long-lasting susceptibility has not been investigated, and it is not known whether specific mechanisms constrain the emergence of resistance. In this study, we first report ß-lactam tolerance due to the inactivation of the c-di-AMP phosphodiesterase GdpP. Mechanistically, tolerance depends on antagonistic regulation by ...[more]

PMID: 38993744

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Dataset Information

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B Streptococcus.

Publications

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B <i>Streptococcus</i>.

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