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There are limited studies so far to describe how a bacterial second messenger molecule can directly participate in distinctive antibiotic tolerance characteristics of a cell in a mechanism-dependent manner. Here we show that intracellular cyclic di-AMP (c-di-AMP) concentration can modulate drug sensitivity of Mycobacterium smegmatis by interacting with an effector protein or interfering with the 5\u2032-UTR regions in mRNA of the genes and thus causing transcriptional downregulation of important genes in the pathways. We studied four antibiotics with different mechanisms of action: rifampicin, ciprofloxacin, erythromycin, and tobramycin and subsequently found that the level of drug sensitivity of the bacteria is directly proportional to the c-di-AMP concentration inside the cell. Further, we unraveled the underlying molecular mechanisms to delineate the specific genes and pathways regulated by c-di-AMP and hence result in differential drug sensitivity in M. smegmatis.<\/jats:p>","DOI":"10.1093\/femsle\/fnae084","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T04:24:45Z","timestamp":1728620685000},"source":"Crossref","is-referenced-by-count":2,"title":["Second messenger c-di-AMP regulates multiple antibiotic sensitivity pathways in <i>Mycobacterium smegmatis<\/i> by discrete mechanisms"],"prefix":"10.1093","volume":"371","author":[{"given":"Aditya Kumar","family":"Pal","sequence":"first","affiliation":[{"name":"Molecular Biophysics Unit, Indian Institute of Science , Bangalore 560012 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipankar","family":"Ghorai","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Unit, Indian Institute of Science , Bangalore 560012 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