{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T16:20:25Z","timestamp":1758039625898,"version":"3.44.0"},"reference-count":58,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35HL135756"],"award-info":[{"award-number":["R35HL135756"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Competence is an important bioprocess for <jats:styled-content style=\"fixed-case\"><jats:italic>Streptococcus pneumoniae<\/jats:italic><\/jats:styled-content>. Previously, we demonstrated that the bacterial second messenger cyclic di\u2010adenosine monophosphate (c\u2010di\u2010AMP) modulates pneumococcal competence. Surprisingly, <jats:italic>cdaA*<\/jats:italic>, a strain producing less c\u2010di\u2010AMP due to a point mutation in the diadenylate cyclase CdaA, is susceptible to competence\u2010stimulating peptide (CSP). In this study, we screened <jats:italic>cdaA<\/jats:italic>* suppressor mutants resistant to CSP to explore the underlying mechanism. Of 14 clones sequenced, nine clones possessed mutations in the c\u2010di\u2010AMP phosphodiesterase Pde1, indicating that the susceptibility to CSP of the <jats:italic>cdaA<\/jats:italic>* strain is correlated to c\u2010di\u2010AMP levels. Another two clones exhibited a mutation in FabT, a transcription factor controlling cell membrane fatty acid biosynthesis. We further showed that deletion of <jats:italic>fabT<\/jats:italic>, disruption of the FabT\u2010binding site within the P<jats:sub><jats:italic>fabK<\/jats:italic><\/jats:sub> promoter, deletion of a <jats:italic>fabT<\/jats:italic> activator BriC, or disruption of K<jats:sup>+<\/jats:sup> uptake in the <jats:italic>cdaA<\/jats:italic>* mutant all rescued the growth defect of the <jats:italic>cdaA<\/jats:italic>* strain in media supplemented with CSP. Finally, we found that a c\u2010di\u2010AMP phosphodiesterase\u2010null mutant with high levels of c\u2010di\u2010AMP is highly sensitive to treatment with either ethanol or Triton X\u2010100, which could be corrected by reducing c\u2010di\u2010AMP levels through introducing point mutations in CdaA. Together, these findings indicate that c\u2010di\u2010AMP affects cell membrane integrity.<\/jats:p>","DOI":"10.1111\/mmi.70003","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T09:40:34Z","timestamp":1751017234000},"page":"230-244","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclic Di\u2010<scp>AMP<\/scp> Affects Cell Membrane Integrity of <i>Streptococcus pneumoniae<\/i>"],"prefix":"10.1111","volume":"124","author":[{"given":"Tiffany M.","family":"Zarrella","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianle","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany New York 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