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However, the molecular mechanisms underlying its high-alcohol production remain unclear. By comparing biological phenotypes of\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      with those of\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      , we found that the former is better at metabolizing high concentrations of glucose, exhibits faster growth rates, and produces higher levels of alcohol, with the 2,3-butanediol (2,3-BD) pathway being the key determinant underlying these differences. More importantly, species possessing the 2,3-BD pathway, including\n                      <jats:italic toggle=\"yes\">Klebsiella aerogenes<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Klebsiella oxytoca<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Enterobacter cloacae<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Enterobacter hormaechei<\/jats:italic>\n                      , have all demonstrated high-alcohol production capabilities similar to that of\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      , suggesting a conserved mechanism for alcohol production among 2,3-BD-positive\n                      <jats:italic toggle=\"yes\">Enterobacteriaceae<\/jats:italic>\n                      . Deletion of the 2,3-BD pathway reduced the expression of the phosphotransferase system (PTS) and the alcohol dehydrogenase gene\n                      <jats:italic toggle=\"yes\">adhE<\/jats:italic>\n                      , which normally confer enhanced glucose metabolism and alcohol production. Pathway deletion also downregulated multiple virulence determinants, including capsular polysaccharides (CPS), lipopolysaccharides (LPS), and type 1 and 3 fimbriae, thereby attenuating virulence in a murine pneumonia model. In addition, the regulator FNR enhanced alcohol production by upregulating\n                      <jats:italic toggle=\"yes\">adhE<\/jats:italic>\n                      and 2,3-BD pathway genes, whereas ArcA activated the 2,3-BD pathway in an ArcB-independent manner, revealing a non-canonical signaling mechanism that couples metabolic adaptation with virulence. Collectively, our findings identify the \u201cFNR\/ArcA\u20132,3-BD pathway axis\u201d as a key molecular mechanism driving high alcohol production in\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      , highlighting the 2,3-BD pathway as a key link between bacterial metabolism and virulence and a potential therapeutic target for controlling\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      infections.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                        has emerged as a novel cause of NAFLD due to its high alcohol-producing capacity. However, the molecular basis of this phenotype remains unclear. In this study, we demonstrate that the FNR\/ArcA-2,3-BD pathway axis drives high levels of alcohol production by enhancing glucose-PTS system and\n                        <jats:italic toggle=\"yes\">adhE<\/jats:italic>\n                        expression, and that this pathway is conserved among\n                        <jats:italic toggle=\"yes\">Enterobacteriaceae<\/jats:italic>\n                        with strong alcohol-producing abilities. Moreover, loss of the 2,3-BD pathway reduces the expression of multiple virulence factors and attenuates pathogenicity in a murine pneumonia model. These findings identify the FNR\/ArcA-2,3-BD axis as a potential target for mitigating excessive alcohol production and virulence in bacteria.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01007-26","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:00:44Z","timestamp":1792069244000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["FNR\/ArcA-2,3-butanediol regulatory axis enhances glucose uptake and\n                    <i>adhE<\/i>\n                    expression in high alcohol-producing\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","author":[{"given":"Zheng","family":"Fan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bacteriology, Capital Center for Children's 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