{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:00:11Z","timestamp":1786370411471,"version":"build-2736575974"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    ) survives host-imposed stress through dynamic metabolic adaptation and growth modulation. Toxin\u2013antitoxin (TA) systems and cell cycle regulators, including RelBE1 and MadR1, are increasingly recognized as contributors to these processes, yet their physiological roles remain unclear. In this perspective, we propose that these systems function as genomically encoded metabolic control modules that couple carbon source availability to persistence. The\n                    <jats:italic>relBE1<\/jats:italic>\n                    loci, encoded adjacent to the \u03b1-ketoglutarate decarboxylase gene (\n                    <jats:italic>kgd<\/jats:italic>\n                    ), and the cell division regulator,\n                    <jats:italic>madR1<\/jats:italic>\n                    , co-localized with the pyruvate dehydrogenase component gene (\n                    <jats:italic>dlaT<\/jats:italic>\n                    ), are transcriptionally linked to key nodes of the tricarboxylic acid (TCA) cycle. Under lipid-rich, host-relevant conditions, these modules may coordinate changes in TCA flux, redox balance, and resource allocation. We suggest that RelBE1 modulates translation in a carbon-state-dependent manner, while MadR1 integrates metabolic signals with growth control. Together, these systems support a regulatory architecture that links environmental sensing to metabolic reprogramming and persistence. This framework reframes TA systems as metabolic integrators and identifies new regulatory components involved in survival during chronic infection.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1863008","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:21:18Z","timestamp":1786368078000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hardwired survival algorithms: RelBE1 and MadR1 couple carbon state to metabolic persistence in Mycobacterium tuberculosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Richard A.","family":"Slayden","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology, and Pathology, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Cummings","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Pathology, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clinton C.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Pathology, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3390\/metabo11020088","article-title":"Metabolic versatility of Mycobacterium tuberculosis during infection and dormancy.","volume":"11","author":"Chang","year":"2021","journal-title":"Metabolites"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e1011143","DOI":"10.1371\/journal.pgen.1011143","article-title":"Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator.","volume":"20","author":"Chen","year":"2024","journal-title":"PLoS Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"14328","DOI":"10.1073\/pnas.251327898","article-title":"RelE, a global inhibitor of translation, is activated during nutritional stress.","volume":"98","author":"Christensen","year":"2001","journal-title":"Proc. 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