{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:44:50Z","timestamp":1778114690460,"version":"3.51.4"},"reference-count":15,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T00:00:00Z","timestamp":1370822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of \u03b2-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose. The affinity between AS and AcrB seemed weaker than that of DHA, while the succinate tail of AS, which was like a \u201cbug\u201d, could extend in the binding pocket very well. Imitating the parent nucleus of DHA and the succinate tail of AS, twenty-one DHA derivatives 4a\u2013u were designed and synthesized. Among them, seventeen were new compounds. The synergistic effects against E. coli AG100A\/pET28a-AcrB showed among the new structures 4k, 4l, 4m, 4n, and 4r exhibited significant synergism with \u03b2-lactam antibiotics although they had no direct antibacterial activities themelves. The bacterial growth assay showed that only 4k in combination with ampicillin or cefuroxime could totally inhibit bacterial growth from 0 to 12 h, demonstrating that 4k had the best antibacterial enhancement effect. In conclusion, our results provided a new idea and several candidate compounds for antibacterial activity enhancers against multidrug resistant E. coli.<\/jats:p>","DOI":"10.3390\/molecules18066866","type":"journal-article","created":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T11:17:56Z","timestamp":1370863076000},"page":"6866-6882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives"],"prefix":"10.3390","volume":"18","author":[{"given":"Chong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xichun","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenying","family":"Xian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dacheng","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Third Military Medical University,  Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2013,6,10]]},"reference":[{"key":"ref_1","first-page":"111","article-title":"Distribution and drug resistance of nosocomial infection bacteria in intensive care Unit","volume":"32","author":"Chen","year":"2011","journal-title":"J. Microbiol."},{"key":"ref_2","first-page":"1843","article-title":"The epidemiological and Drug-resistant study of pathogenic bacteria in Intensive Care Unit","volume":"40","author":"Tu","year":"2011","journal-title":"Chongqing Med."},{"key":"ref_3","first-page":"1843","article-title":"The epidemiological and Drug-resistant study of pathogenic bacteria in Intensive Care Unit","volume":"40","author":"Tu","year":"2011","journal-title":"Chongqing Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.mib.2009.07.003","article-title":"Structure, function and inhibition of RND efflux pumps in Gram-negative bacteria: an update","volume":"12","author":"Blair","year":"2009","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.bbapap.2008.10.004","article-title":"Mechanisms of RND multidrug efflux pumps","volume":"1794","author":"Nikaido","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1073\/pnas.1114944109","article-title":"Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop","volume":"109","author":"Eicher","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nature01050","article-title":"Crystal structure of bacterial multidrug efflux transporter AcrB","volume":"419","author":"Murakami","year":"2002","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jmb.2012.06.036","article-title":"Assembling of AcrB trimer in cell membrane","volume":"423","author":"Lu","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1365-2958.2010.07330.x","article-title":"Substrate path in the AcrB multidrug efflux pump of Escherichia coli","volume":"78","author":"Husain","year":"2010","journal-title":"Mol. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/oxfordjournals.jbchem.a003069","article-title":"Membrane topology of a multidrug efflux transporter, AcrB, in Escherichia col","volume":"131","author":"Fujihira","year":"2002","journal-title":"J. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.bbapap.2008.12.015","article-title":"Drug transport mechanism of the AcrB efflux pump","volume":"1794","author":"Pos","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/jac\/dkr017","article-title":"Artesunate enhances the antibacterial effect of \u03b2-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC","volume":"66","author":"Li","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nature10641","article-title":"Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket","volume":"480","author":"Nakashima","year":"2011","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6559","DOI":"10.1073\/pnas.1001460107","article-title":"Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli","volume":"107","author":"Takatsuka","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1371\/journal.pbio.0050007","article-title":"Drug export pathway of multidrug exporter AcrB revealed by DARP in inhibitors","volume":"5","author":"Sennhauser","year":"2007","journal-title":"PLoS Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/6\/6866\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:47:17Z","timestamp":1760219237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/6\/6866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,10]]},"references-count":15,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2013,6]]}},"alternative-id":["molecules18066866"],"URL":"https:\/\/doi.org\/10.3390\/molecules18066866","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,10]]}}}