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This study identifies the anticancer agent mitoxantrone as a potent antimicrobial against\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      . Through passaging experiments, we demonstrate that resistance to mitoxantrone arises via mutations in the\n                      <jats:italic toggle=\"yes\">kstR2<\/jats:italic>\n                      gene, leading to the overexpression of the SmvA efflux pump. Transcriptomic analysis reveals that mitoxantrone treatment induces the bacterial SOS response, likely due to DNA damage. Critically, we found that mitoxantrone exhibits a synergistic effect with tigecycline against\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      , both\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and in a murine wound infection model. Mechanistically, this synergy is driven by tigecycline-mediated enhancement of intracellular mitoxantrone accumulation. These findings reveal a potentially effective combination regimen to combat\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                        The rise of antibiotic-resistant\n                        <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                        demands new treatment options. This study uncovers that mitoxantrone, a drug currently approved for cancer therapy, is effective against\n                        <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                        . Furthermore, we discovered that combining mitoxantrone with the existing antibiotic tigecycline is synergistic against\n                        <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                        . We found that tigecycline enhances mitoxantrone accumulation inside bacterial cells. Overall, our work identified the tigecycline-mitoxantrone combination as a promising strategy to treat\n                        <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                        infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00568-26","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T13:03:54Z","timestamp":1786539834000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Mitoxantrone synergies with tigecycline against\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7775-2128","authenticated-orcid":false,"given":"Xin","family":"Xia","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoya","family":"Wei","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuiping","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04gw3ra78","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine, Fifth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Cheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1449-6735","authenticated-orcid":true,"given":"Yongxin","family":"Jin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouguang","family":"Jin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9017-0091","authenticated-orcid":true,"given":"Weihui","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y1kjr75","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.21588"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanmic.2024.07.010"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14649"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2011.02.003"},{"key":"e_1_3_5_7_2","unstructured":"World Health Organization. 2024. 2023 antibacterial agents in clinical and preclinical development: an overview and analysis. 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