{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:10:43Z","timestamp":1788959443611,"version":"build-2803163510"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100017054","name":"National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization","doi-asserted-by":"publisher","award":["ZCLZ26C0101"],"award-info":[{"award-number":["ZCLZ26C0101"]}],"id":[{"id":"10.13039\/100017054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170044"],"award-info":[{"award-number":["32170044"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The escalating threat of antimicrobial resistance in\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      necessitates novel therapeutic vulnerabilities. Here, we identify the redox-sensing regulator SoxR as a specific target of zinc toxicity and reveal that SoxR regulatory networks differ fundamentally even among closely related Enterobacteriaceae. Integrated\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      analyses show that zinc competitively displaces the essential SoxR [2Fe\u20132S] cluster, causing protein destabilization and functional inactivation. Consequently, bacteria fail to activate the canonical soxS\u2013sodA defense axis, rendering them hypersensitive to vitamin K3-induced superoxide stress. Building on this mechanism, we established a synergistic strategy combining zinc with vitamin K3. This combination elicited potent bactericidal activity against\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      (including ciprofloxacin-resistant strains) and\n                      <jats:italic toggle=\"yes\">Salmonella<\/jats:italic>\n                      Typhimurium, with a remarkably low propensity for resistance development. Furthermore, treatment significantly improved survival in a\n                      <jats:italic toggle=\"yes\">Galleria mellonella<\/jats:italic>\n                      acute infection model without detectable host toxicity. Collectively, highlighting SoxR [2Fe\u20132S] cluster integrity as a critical vulnerability, this work extends metal\u2013redox crosstalk-based antibacterial intervention from\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      to a clinically important pathogen and provides a conceptual framework for developing redox-targeting therapies against drug-resistant gram-negative bacteria.\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                        is a major drug-resistant pathogen whose survival in the host depends heavily on its ability to withstand oxidative stress. While the SoxR\/SoxS system is well characterized in\n                        <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                        , whether SoxR functions similarly in\n                        <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                        and whether it can be selectively targeted have remained unknown. Here, we show that the SoxR regulatory network displays clear species-dependent features: sequence comparison reveals low homology of\n                        <jats:italic toggle=\"yes\">soxS<\/jats:italic>\n                        between the two organisms, and SoxR function cannot be simply interchanged across them. Importantly, we demonstrate for the first time that Zn\u00b2\n                        <jats:sup>+<\/jats:sup>\n                        specifically targets\n                        <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                        SoxR by directly and competitively disrupting its essential [2Fe\u20132S] cluster, leading to protein instability, loss of redox regulatory function, and heightened sensitivity to oxidative stress. This previously unrecognized metal\u2013redox interference mechanism exposes a conserved biochemical vulnerability in oxidative defense and provides a mechanistic basis for developing nontraditional antibacterial strategies that exploit intrinsic stress-response weaknesses rather than conventional growth targets.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01146-26","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:01:46Z","timestamp":1785330106000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Conserved vulnerability of SoxR underlies zinc-mediated redox disruption and synergistic killing in\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4145-8037","authenticated-orcid":true,"given":"Jie","family":"Feng","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rd5t069","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Medicine, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxiao","family":"Tong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rd5t069","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Medicine, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University","place":["Wenzhou, 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