{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:57:21Z","timestamp":1790294241094,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The emergence and spread of the<jats:italic>mcr-1<\/jats:italic>gene and its mutants has immensely compromised the efficient usage of colistin for the treatment of drug-resistant Gram-negative bacterial infection in clinical settings. However, there are currently no clinically available colistin synergis. Here we identify artemisinin derivatives, such as dihydroartemisinin (DHA), that produces a synergistic antibacterial effect with colistin against the majority of Gram-negative bacteria (FIC\u2009&lt;\u20090.5) without induced resistance, particularly those carrying the<jats:italic>mcr-1<\/jats:italic>gene. Mechanism analysis reveals the direct engagement of DHA with the active center of MCR-1 to inhibit the activity of MCR-1. Meanwhile, the results from transcriptome and electron microscope analysis show that DHA could also simultaneously affect the flagellar assembly and the energy metabolism of bacteria. Moreover, in the mouse infection models of Gram-negative bacteria, combination therapy shows remarkable treatment benefits, as shown by an improved survival rate, reduced morbidity, alleviated pathological injury and decreased bacterial loading. Due to the generally safe profile of specialized malaria medication administration in humans, artemisinin derivatives are a promising class of multi-target inhibitors on bacterial resistance and virulence that can be used to extend the usage life of colistin and to tackle the inevitability of serious bacterial infection with colistin.<\/jats:p>","DOI":"10.1038\/s42003-022-03898-5","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T17:04:00Z","timestamp":1662656640000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Commercialized artemisinin derivatives combined with colistin protect against critical Gram-negative bacterial infection"],"prefix":"10.1038","volume":"5","author":[{"given":"Yonglin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baichen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuling","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqing","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuming","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3036-2374","authenticated-orcid":false,"given":"Dan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianghua","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8311-0894","authenticated-orcid":false,"given":"Jianfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"3898_CR1","doi-asserted-by":"publisher","first-page":"16260","DOI":"10.1038\/nmicrobiol.2016.260","volume":"2","author":"Y Wang","year":"2017","unstructured":"Wang, Y. et al. Comprehensive resistome analysis reveals the prevalence of NDM and MCR-1 in Chinese poultry production. Nat. Microbiol. 2, 16260 (2017).","journal-title":"Nat. Microbiol."},{"key":"3898_CR2","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S1473-3099(15)00424-7","volume":"16","author":"YY Liu","year":"2015","unstructured":"Liu, Y. Y. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet 16, 161\u2013168 (2015).","journal-title":"Lancet"},{"key":"3898_CR3","doi-asserted-by":"publisher","first-page":"e20190237","DOI":"10.1590\/0037-8682-0237-2019","volume":"52","author":"F Hameed","year":"2019","unstructured":"Hameed, F. et al. Plasmid-mediated mcr-1 gene in Acinetobacter baumannii and Pseudomonas aeruginosa: first report from Pakistan. Rev. da Soc. Brasileira de. Med. Tropical. 52, e20190237 (2019).","journal-title":"Rev. da Soc. Brasileira de. Med. Tropical."},{"key":"3898_CR4","first-page":"e02317","volume":"9","author":"Y Xu","year":"2018","unstructured":"Xu, Y. et al. An evolutionarily conserved mechanism for intrinsic and transferable polymyxin resistance. Mbio 9, e02317\u201317 (2018).","journal-title":"Mbio"},{"key":"3898_CR5","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1080\/22221751.2022.2036078","volume":"11","author":"X Liu","year":"2022","unstructured":"Liu, X. et al. Emergence of colistin-resistant hypervirulent Klebsiella pneumoniae (CoR-HvKp) in China. Emerg. Microbes Infect. 11, 648\u2013661 (2022).","journal-title":"Emerg. Microbes Infect."},{"key":"3898_CR6","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1046\/j.1469-0691.2002.00394.x","volume":"8","author":"H Pituch","year":"2002","unstructured":"Pituch, H. et al. Variable flagella expression among clonal toxin A-\/B+Clostridium difficile strains with highly homogeneous flagellin genes. Clin. Microbiol. Infect. 8, 187\u20138 (2002).","journal-title":"Clin. Microbiol. Infect."},{"key":"3898_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2016.82","volume":"5","author":"G Luo","year":"2016","unstructured":"Luo, G. et al. flrA, flrB and flrC regulate adhesion by controlling the expression of critical virulence genes in Vibrio alginolyticus. Emerg. Microbes Infect. 5, e85 (2016).","journal-title":"Emerg. Microbes Infect."},{"key":"3898_CR8","doi-asserted-by":"crossref","unstructured":"Green, C. A. et al. Engineering the flagellar type III secretion system: improving capacity for secretion of recombinant protein. Microbial Cell Factories 18, 10 (2019).","DOI":"10.1186\/s12934-019-1058-4"},{"key":"3898_CR9","doi-asserted-by":"publisher","first-page":"10210","DOI":"10.1002\/anie.201601967","volume":"47","author":"Y Tu","year":"2016","unstructured":"Tu, Y. Artemisinin-a gift from traditional Chinese medicine to the world (Nobel Lecture). Angew. Chem. 47, 10210\u201310226 (2016).","journal-title":"Angew. Chem."},{"key":"3898_CR10","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1111\/j.1469-0691.2011.03660.x","volume":"17","author":"RD Gosling","year":"2011","unstructured":"Gosling, R. D., Okell, L., Mosha, J. & Chandramohan, D. The role of antimalarial treatment in the elimination of malaria. Clin. Microbiol Infect. 17, 1617\u201323 (2011).","journal-title":"Clin. Microbiol Infect."},{"key":"3898_CR11","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1517\/14728214.2012.702754","volume":"17","author":"S Tschan","year":"2012","unstructured":"Tschan, S., Kremsner, P. G. & Mordm\u00fcller, B. Emerging drugs for malaria. Expert Opin. Emerg. Drugs 17, 319\u201333 (2012).","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"3898_CR12","doi-asserted-by":"crossref","unstructured":"Li G. Q. at al. Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Transactions of the Royal Society of Tropical Medicine & Hygiene. (Supplement_1), S5-6 (1994).","DOI":"10.1016\/0035-9203(94)90460-X"},{"key":"3898_CR13","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1046\/j.1365-2125.2003.01986.x","volume":"57","author":"S Mithwani","year":"2004","unstructured":"Mithwani, S. et al. Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria. Br. J. Clin. Pharmacol. 57, 146\u2013152 (2004).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"3898_CR14","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1111\/1440-1681.13461","volume":"48","author":"Y Chen","year":"2021","unstructured":"Chen, Y. et al. Dihydroartemisinin attenuated the symptoms of mice model of systemic lupus erythematosus by restoring the Treg\/Th17 balance. Clin. Exp. Pharmacol. Physiol. 48, 626\u2013633 (2021).","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"3898_CR15","doi-asserted-by":"publisher","first-page":"104901","DOI":"10.1016\/j.phrs.2020.104901","volume":"158","author":"D Cheong","year":"2020","unstructured":"Cheong, D. et al. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol. Res. 158, 104901 (2020).","journal-title":"Pharmacol. Res."},{"key":"3898_CR16","doi-asserted-by":"crossref","unstructured":"Efferth, T. From ancient herb to versatile, modern drug: Artemisia annua and artemisinin for cancer therapy. Semin. Cancer Biol. S1044579X17300299 (2017).","DOI":"10.1016\/j.semcancer.2017.02.009"},{"key":"3898_CR17","doi-asserted-by":"crossref","unstructured":"Guo, Y. et al. Honokiol restores polymyxin susceptibility to MCR-1-positive pathogens both in vitro and in vivo. Appl. Environ. Microbiol. 86, e02346 (2019).","DOI":"10.1128\/AEM.02346-19"},{"key":"3898_CR18","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.jinf.2019.03.004","volume":"78","author":"Y Zhou","year":"2019","unstructured":"Zhou, Y. et al. Discovery of a potential MCR-1 inhibitor that reverses polymyxin activity against clinical mcr-1-positive Enterobacteriaceae. J. Infect. 78, 364\u2013372 (2019).","journal-title":"J. Infect."},{"key":"3898_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04288-4","volume":"9","author":"Z Zhao","year":"2018","unstructured":"Zhao, Z. et al. Flagella elongation revealed by single cell real-time fluorescence imaging. Nat. Commun. 9, 1885 (2018).","journal-title":"Nat. Commun."},{"key":"3898_CR20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s42003-020-0877-5","volume":"3","author":"Y Liu","year":"2020","unstructured":"Liu, Y. et al. Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli. Commun. Biol. 3, 162 (2020).","journal-title":"Commun. Biol."},{"key":"3898_CR21","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41581-019-0150-7","volume":"15","author":"TZ Wang","year":"2019","unstructured":"Wang, T. Z., Kodiyanplakkal, R. P. L. & Calfee, D. P. Antimicrobial resistance in nephrology. Nat. Rev. Nephrol. 15, 463\u2013481 (2019).","journal-title":"Nat. Rev. Nephrol."},{"key":"3898_CR22","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ebiom.2017.10.003","volume":"25","author":"M Vafa Homann","year":"2017","unstructured":"Vafa Homann, M. et al. Detection of malaria parasites after treatment in travelers: a 12-months longitudinal study and statistical modelling analysis. EBioMedicine 25, 66\u201372 (2017).","journal-title":"EBioMedicine"},{"key":"3898_CR23","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.2174\/13895575113136660097","volume":"13","author":"MT Ansari","year":"2013","unstructured":"Ansari, M. T. et al. Malaria and artemisinin derivatives:an updated review. Mini Rev. Med. Chem. 13, 1879\u20131902 (2013).","journal-title":"Mini Rev. Med. Chem."},{"key":"3898_CR24","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1016\/j.cmi.2020.02.004","volume":"26","author":"NM Smith","year":"2020","unstructured":"Smith, N. M. et al. Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii. Clin. Microbiol. Infect. 26, 1207\u20131213 (2020).","journal-title":"Clin. Microbiol. Infect."},{"key":"3898_CR25","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/phar.2209","volume":"39","author":"BT Tsuji","year":"2019","unstructured":"Tsuji, B. T. et al. International Consensus Guidelines for the Optimal Use of the Polymyxins.: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy 39, 10\u201339 (2019).","journal-title":"Pharmacotherapy"},{"key":"3898_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/22221751.2020.1769499","volume":"9","author":"ES Ahmed","year":"2020","unstructured":"Ahmed, E. S. et al. Colistin and its role in the Era of antibiotic resistance: an extended review (2000\u20132019). Emerg. Microbes Infect. 9, 1\u201361 (2020).","journal-title":"Emerg. Microbes Infect."},{"key":"3898_CR27","first-page":"e02146","volume":"62","author":"Y Zhou","year":"2018","unstructured":"Zhou, Y. et al. Pterostilbene, a potential MCR-1 inhibitor that enhances the efficacy of polymyxin B. Antimicrobial Agents Chemother. 62, e02146 (2018).","journal-title":"Antimicrobial Agents Chemother."},{"key":"3898_CR28","unstructured":"CLSI, Performance standards for antimicrobial susceptibility testing. Nccls Document M S (2012)."},{"key":"3898_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jac\/dkg301","volume":"52","author":"FC Odds","year":"2003","unstructured":"Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52, 1 (2003).","journal-title":"J. Antimicrob. Chemother."},{"key":"3898_CR30","doi-asserted-by":"publisher","first-page":"1902227","DOI":"10.1002\/advs.201902227","volume":"7","author":"Y Liu","year":"2020","unstructured":"Liu, Y. et al. Metformin restores tetracyclines susceptibility against multidrug resistant bacteria. Adv. Sci. 7, 1902227 (2020).","journal-title":"Adv. Sci."},{"key":"3898_CR31","doi-asserted-by":"crossref","unstructured":"Lv, Q. at al. Inhibition of the type III secretion system by syringaldehyde protects mice from Salmonella enterica serovar Typhimurium. J. Cell. Mol. Med. 23, 4679-4688 (2019).","DOI":"10.1111\/jcmm.14354"},{"key":"3898_CR32","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","volume":"31","author":"O Trott","year":"2009","unstructured":"Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455\u2013461 (2009).","journal-title":"J. Comput. Chem."},{"key":"3898_CR33","first-page":"57","volume":"17","author":"MF Sanner","year":"1998","unstructured":"Sanner, M. F. Python: a programming language for software integration and development. J. Mol. Graph. Model. 17, 57\u201361 (1998).","journal-title":"J. Mol. Graph. Model."},{"key":"3898_CR34","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"30","author":"GM Morris","year":"2009","unstructured":"Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Computational Chem. 30, 2785\u201391 (2009).","journal-title":"J. Computational Chem."},{"key":"3898_CR35","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1021\/ct400314y","volume":"9","author":"R Salomon-Ferrer","year":"2013","unstructured":"Salomon-Ferrer, R. et al. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh ewald. J. Chem. Theory Comput. 9, 3878\u20133888 (2013).","journal-title":"J. Chem. Theory Comput."},{"key":"3898_CR36","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","volume":"25","author":"J Wang","year":"2006","unstructured":"Wang, J. et al. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 25, 247\u201360 (2006).","journal-title":"J. Mol. Graph. Model."},{"key":"3898_CR37","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1093\/jac\/dkq226","volume":"65","author":"RV Dudhani","year":"2010","unstructured":"Dudhani, R. V., Turnidge, J. D. & Nation, R. L. fAUC\/MIC is the most predictive pharmacokinetic\/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models. J. Antimicrobial Chemother. 65, 1984\u20131990 (2010).","journal-title":"J. Antimicrobial Chemother."},{"key":"3898_CR38","doi-asserted-by":"publisher","first-page":"e01315","DOI":"10.1128\/mBio.01315-17","volume":"8","author":"SM Daly","year":"2017","unstructured":"Daly, S. M., Sturge, C. R., Felder-Scott, C. F., Geller, B. L. & Greenberg, D. E. mcr-1 inhibition with peptide-conjugated phosphorodiamidate morpholino oligomers restores sensitivity to polymyxin in Escherichia coli. Mbio 8, e01315\u201317 (2017).","journal-title":"Mbio"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-022-03898-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-022-03898-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-022-03898-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,26]],"date-time":"2023-11-26T19:03:02Z","timestamp":1701025382000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-022-03898-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["3898"],"URL":"https:\/\/doi.org\/10.1038\/s42003-022-03898-5","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]},"assertion":[{"value":"11 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"931"}}