{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:44:31Z","timestamp":1753883071294,"version":"3.41.2"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R01AI116605"],"award-info":[{"award-number":["R01AI116605"]}]},{"DOI":"10.13039\/100011138","name":"AgBioResearch, Michigan State University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100011138","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Mycobacteria can colonize environments where the availability of metal ions is limited. Biological or inorganic chelators play an important role in limiting metal availability, and we developed a model to examine\n            <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n            survival in the presence of the chelator sodium citrate. We observed that instead of restricting\n            <jats:italic>M. smegmatis<\/jats:italic>\n            growth, concentrated sodium citrate killed\n            <jats:italic>M. smegmatis<\/jats:italic>\n            . RNAseq analysis during sodium citrate treatment revealed transcriptional signatures of metal starvation and hyperosmotic stress. Notably, metal starvation and hyperosmotic stress, individually, do not kill\n            <jats:italic>M. smegmatis<\/jats:italic>\n            under these conditions. A forward genetic transposon selection was conducted to examine why sodium citrate was lethal, and several sodium-citrate-tolerant mutants were isolated. Based on the identity of three tolerant mutants,\n            <jats:italic>mgtE<\/jats:italic>\n            ,\n            <jats:italic>treZ<\/jats:italic>\n            , and\n            <jats:italic>fadD6,<\/jats:italic>\n            we propose a dual stress model of killing by sodium citrate, where sodium citrate chelate metals from the cell envelope and then osmotic stress in combination with a weakened cell envelope causes cell lysis. This sodium citrate tolerance screen identified mutants in several other genes with no known function, with most conserved in the pathogen\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            . Therefore, this model will serve as a basis to define their functions, potentially in maintaining cell wall integrity, cation homeostasis, or osmotolerance.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Bacteria require mechanisms to adapt to environments with differing metal availability. When\n              <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n              is treated with high concentrations of the metal chelator sodium citrate, the bacteria are killed. To define the mechanisms underlying killing by sodium citrate, we conducted a genetic selection and observed tolerance to killing in mutants of the\n              <jats:italic>mgtE<\/jats:italic>\n              magnesium transporter. Further characterization studies support a model where killing by sodium citrate is driven by a weakened cell wall and osmotic stress, that in combination cause cell lysis.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00358-23","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T13:02:08Z","timestamp":1694178128000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A genetic selection for\n            <i>Mycobacterium smegmatis<\/i>\n            mutants tolerant to killing by sodium citrate defines a combined role for cation homeostasis and osmotic stress in cell death"],"prefix":"10.1128","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2742-1636","authenticated-orcid":false,"given":"John T.","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University 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Lansing, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Murto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica J.","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haleigh N.","family":"Gilliland","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Olive","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4119-4169","authenticated-orcid":false,"given":"Robert B.","family":"Abramovitch","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, 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