Molecular Microbiology (@molmicrounihoh.bsky.social)

c-di-AMP–DasR signaling axis mediates mycobacterial acid resistance | mBio The findings identified a regulatory axis central to mycobacterial acid adaptation, and DasR was found to be a conserved c-di-AMP receptor in Mycobacterium tuberculosis. A key feature is its highly pH-sensitive binding to c-di-AMP, which exhibits a 20-fold increase in affinity under acidic conditions, indicating that environmental cues are linked to the transcriptional response. DasR directly targets genes governing (p)ppGpp, cyclic AMP (cAMP), c-di-AMP metabolism, and acid adaptation, creating a feedback loop that dynamically balances stress signaling pathways. The concurrent upregulation of the chaperone HtpG stabilizes the DasR complex, increasing signal output under stress. This integrated system, which combines allosteric enhancement of DNA binding with chaperone-mediated stabilization, constitutes an evolutionarily refined strategy for acid resistance. The c-di-AMP–DasR pathway is therefore a promising target that could enable researchers to address the persistence of M. tuberculosis. https://journals.asm.org/doi/10.1128/mbio.03708-25