{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:20:39Z","timestamp":1787163639667,"version":"build-2736575974"},"reference-count":62,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,10,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The plasmid-mediated gene mcr-1 that makes bacteria resistant to the antibiotic colistin is spreading quickly, which means that colistin is no longer working well to treat Gram-negative bacterial infections. Herein, we utilized a computer-aided high-throughput screening drugs method to identify the natural product apigenin, a potential\n                      <jats:italic>mcr<\/jats:italic>\n                      -protein inhibitor, which effectively enhanced the antimicrobial activity of colistin. Several assays, including a checkerboard minimum inhibitory concentration assay, a time-kill assay, the combined disk test, molecular simulation dynamics, and animal infection models assay, were conducted to verify whether apigenin enhanced the ability of colistin to fight Gram-negative bacterial infections. The results showed that apigenin improved the antimicrobial activity of colistin against multidrug-resistant\n                      <jats:italic>Enterobacteriaceae<\/jats:italic>\n                      infection. Moreover, apigenin not only did not increase the toxic effect of colistin but also had the ability to effectively inhibit the frequency of bacterial resistance mutations to colistin. Studies clearly elucidated that apigenin could interfere with the thermal stability of the protein by binding to the\n                      <jats:italic>mcr<\/jats:italic>\n                      -1 protein. Additionally, the combination of apigenin and colistin could exert multiple effects, including disrupting bacterial membranes, the generation of bacterial nitric oxide and reactive oxygen species, as well as inhibiting bacterial adenosine triphosphate production. Furthermore, the addition of apigenin was able to significantly inhibit colistin-stimulated high expression levels of the bacterial mcr-1 gene. Finally, apigenin exhibited a characteristic anti-inflammatory effect while enhancing the antimicrobial activity of colistin against mcr-1-positive\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (\n                      <jats:italic>E. coli<\/jats:italic>\n                      ) infected animals. In conclusion, as a potential lead compound, apigenin is promising in combination with colistin in the future treatment of mcr-1-positive\n                      <jats:italic>E. coli<\/jats:italic>\n                      infections.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study found that apigenin was able to inhibit the activity of the\n                        <jats:italic>mcr<\/jats:italic>\n                        -1 protein using a high-throughput virtual screening method. Apigenin effectively enhanced the antimicrobial activity of colistin against multidrug-resistant\n                        <jats:italic>Enterobacteriaceae<\/jats:italic>\n                        , including mcr-1-positive strains,\n                        <jats:italic>in vitro<\/jats:italic>\n                        and\n                        <jats:italic>in vivo<\/jats:italic>\n                        . This study will provide new options and strategies for the future treatment of multidrug-resistant pathogen infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00341-24","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T09:00:55Z","timestamp":1725872455000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["High-throughput screening identification of apigenin that reverses the colistin resistance of mcr-1-positive pathogens"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2024-8121","authenticated-orcid":false,"given":"Feng","family":"Tang","sequence":"first","affiliation":[{"name":"College of Animal Science and Veterinary Medicine, Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Peng","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine, Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Kou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine, Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4765-184X","authenticated-orcid":false,"given":"Zeliang","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine, Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5298-6181","authenticated-orcid":false,"given":"Libo","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine, Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101221"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2015.199"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro727"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2017.28"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00117-14"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.21647"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00424-7"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00010-4"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3975"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-023-00629-8"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00109"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2016.72"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00466-1"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.559"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.11.5.852"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13050625"},{"key":"e_1_3_4_19_2","first-page":"159","article-title":"Rediscovering natural products as a source of new drugs","volume":"5","author":"Koehn FE","year":"2005","unstructured":"Koehn FE, Carter GT. 2005. 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