{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:15:50Z","timestamp":1788225350503,"version":"build-2803163510"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Shanghai Agricultural Science and Technology Innovation Project","award":["2025-02-08-00-12-F00026"],"award-info":[{"award-number":["2025-02-08-00-12-F00026"]}]},{"name":"Key Research and Development Program of the Science and Technology Plan in the Tibet Autonomous Region","award":["XZ202401ZY0052"],"award-info":[{"award-number":["XZ202401ZY0052"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Colistin remains a last-line antibiotic against multidrug-resistant Gram-negative pathogens, but its clinical utility is limited by nephrotoxicity and emerging resistance. This study identifies macelignan, a natural lignan from nutmeg, as a potent synergist that enhances colistin activity against\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      ) through a novel metabolic disruption mechanism.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , macelignan reduced the colistin minimum inhibitory concentration (MIC) by approximately 100-fold, with the combination (8 \u00b5g\/mL macelignan + 0.008 \u00b5g\/mL colistin) achieving complete bacterial eradication within 4 h.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , combination therapy significantly reduced bacterial burden in a mouse thigh infection model (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05). Mechanistic studies revealed that macelignan disrupts bacterial energy metabolism by inhibiting the citric acid cycle, leading to ATP depletion. This energy compromise impairs the bacterial capacity to repair colistin-induced membrane damage, exacerbating membrane disruption and accelerating bacterial death. These findings establish macelignan as a promising adjuvant for colistin-based therapy and elucidate a dual \u201cinternal and external pincer\u201d mechanism that could inform future antibiotic combination strategies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The continued efficacy of colistin, a last-line antibiotic against multidrug-resistant Gram-negative pathogens, is increasingly threatened by dose-limiting nephrotoxicity and the global spread of resistance determinants. This study introduces macelignan\u2014a naturally occurring lignan from nutmeg\u2014as a highly effective colistin adjuvant that operates through a previously unrecognized mechanism centered on metabolic disruption. By targeting the bacterial citric acid cycle, macelignan depletes intracellular ATP, thereby crippling the energy-dependent machinery required for membrane repair following colistin-induced damage. This dual \u201cinternal and external pincer\u201d strategy not only dramatically reduces the colistin concentration needed for bactericidal activity but also significantly lowers bacterial burden\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . These findings provide a mechanistic framework for developing metabolism-targeting adjuvants to revitalize last-resort antibiotics and expand the therapeutic arsenal against recalcitrant Gram-negative infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01129-26","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T13:03:01Z","timestamp":1781096581000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>In vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    enhancement of colistin activity against\n                    <i>Escherichia coli<\/i>\n                    strains by 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