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It is unknown whether\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  also requires riboflavin synthesis to grow or persist in infected host cells or tissues. Here we used a\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  strain that conditionally expresses\n                  <jats:italic>ribA2<\/jats:italic>\n                  , which encodes a bifunctional enzyme that catalyzes the first steps in both branches of riboflavin biosynthesis, to determine whether\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  requires riboflavin biosynthesis during infection. Transcriptional repression of\n                  <jats:italic>ribA2<\/jats:italic>\n                  caused death of\n                  <jats:italic>M. tuberculosis in vitro<\/jats:italic>\n                  without riboflavin supplementation. RNAseq revealed that riboflavin starved\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  induce a transcriptional program indicating decreased electron transport chain function and broad changes to central metabolism. Transcriptional repression of\n                  <jats:italic>ribA2<\/jats:italic>\n                  prevented\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  growth in cultured macrophages and caused clearance of\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  from infected tissues at all stages of infection in both C57BL\/6 mice that form cellular lung lesions and C3HeB\/FeJ mice that develop necrotic lung granulomas. Our results demonstrate that\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  requires RibA2 for viability at all stages of infection and support further characterization of the riboflavin biosynthesis pathway as a potential target for development of new anti-tubercular drugs.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>AUTHOR SUMMARY<\/jats:title>\n                  <jats:p>\n                    Tuberculosis (TB) caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    kills over 1.2 million people worldwide each year, making it the deadliest bacterial infection. TB treatment involves combinations of antibiotics taken for at least six months.\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    readily becomes resistant to antibiotics by mutation and multidrug resistant strains account for nearly 4% of new TB cases. New antibiotics for TB are needed to combat drug resistance and shorten TB treatment. Riboflavin biosynthesis is an attractive target for antibiotic development because mammals do not synthesize riboflavin, instead obtaining it from the diet. Here, using a\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    strain that conditionally expresses the riboflavin biosynthesis enzyme RibA2, we show that inhibition of riboflavin biosynthesis kills\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    in lab culture conditions and in mice at all stages of infection. Our results demonstrate that riboflavin starvation is bactericidal for\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    and identify the riboflavin biosynthesis pathway as a promising target for new drugs to treat TB.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.25.754416","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:40:11Z","timestamp":1790476811000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Mycobacterium tuberculosis<\/i>\n                  requires riboflavin biosynthesis for survival in the host"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0987-9181","authenticated-orcid":false,"given":"Alisha M.","family":"Block","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah B.","family":"Namugenyi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8404-0250","authenticated-orcid":false,"given":"Anna D.","family":"Tischler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026093005050467000_2026.09.25.754416v1.1","unstructured":"WHO. 2025. 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