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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 uncertain whether specific mechanisms constraint the emergence of resistance. In this study, we first report a conserved role of the signaling nucleotide cyclic-di-AMP in the sensitivity of S. agalactiae to ß-lactam. Specifically, we demonstrate that inactivation of the phosphodiesterase GdpP confers ß-lactam tolerance. Characterizing the signaling pathway revealed an antagonistic regulation by the transcriptional factor BusR, which is activated by c-di-AMP and negatively regulates ß-lactam susceptibility. Furthermore, we show that simultaneous inhibition of osmolyte transporters activity and transcription by c-di-AMP has an additive effect, sustaining ß-lactam tolerance. Finally, transposon mutagenesis for ß-lactam reduced susceptibility reveals a convergent pattern of mutations, including in the KhpAB small RNA chaperone and the protein S immunomodulator. Overall, our findings suggest mechanisms that may foster antibiotic resistance in S. agalactiae and demonstrate that c-di-AMP acts as a turgor pressure rheostat, coordinating an integrated response to cell wall weakening due to ß-lactam activity.

ORGANISM(S): Streptococcus agalactiae Streptococcus agalactiae NEM316

PROVIDER: GSE262190 | GEO | 2024/04/25

REPOSITORIES: GEO

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