{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:57:12Z","timestamp":1789811832592,"version":"4.0.1"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,2,22]],"date-time":"2018-02-22T00:00:00Z","timestamp":1519257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003621","name":"Ministry of Science, ICT and Future Planning","doi-asserted-by":"publisher","award":["2012R1A1B5002680"],"award-info":[{"award-number":["2012R1A1B5002680"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aim<\/jats:title><jats:p><jats:italic>rdxA<\/jats:italic> and <jats:italic>frxA<\/jats:italic> mutations and enhancement of efflux pump have been suggested as the cause of metronidazole resistance in <jats:italic>Helicobacter pylori<\/jats:italic>. This study was performed to investigate the resistance mechanisms related to clinical eradication outcome, and to examine direct involvement of <jats:italic>hefA<\/jats:italic> in metronidazole\u2010resistant isolates with intact <jats:italic>rdxA<\/jats:italic> and <jats:italic>frxA<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 53 <jats:italic>H.\u00a0pylori<\/jats:italic>\u2010positive patients who were treated with metronidazole\u2010containing sequential or quadruple therapy from 2011 to 2015 were enrolled. The metronidazole susceptibility of <jats:italic>H.\u00a0pylori<\/jats:italic> isolates was examined by agar dilution test. Mutations in <jats:italic>rdxA<\/jats:italic> and <jats:italic>frxA,<\/jats:italic> were analyzed with DNA sequencing, and impact of <jats:italic>hefA<\/jats:italic> on metronidazole resistance was examined with quantitative real\u2010time reverse transcription polymerase chain reaction, knockout and genetic complementation test for <jats:italic>hefA<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seven mutation types of <jats:italic>rdxA<\/jats:italic> and\/or <jats:italic>frxA<\/jats:italic> were found in <jats:italic>H.\u00a0pylori<\/jats:italic> isolated from non\u2010eradicated subjects. <jats:italic>rdxA<\/jats:italic> mutation was associated with eradication failure (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.002), and nonsense mutation in <jats:italic>rdxA<\/jats:italic> reduced eradication efficacy (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.009). <jats:italic>hefA<\/jats:italic> expression was significantly higher in resistant isolates (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), especially in <jats:italic>rdxA(\u2212)frxA(\u2212)<\/jats:italic> as compared to <jats:italic>rdxA(+)frxA(+)<\/jats:italic> (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.027). Resistant isolates with no mutation in <jats:italic>rdxA<\/jats:italic> and <jats:italic>frxA<\/jats:italic> became susceptible after <jats:italic>hefA<\/jats:italic> knockout. Genetic complementation for <jats:italic>hefA<\/jats:italic> recovered metronidazole resistance in all of three <jats:italic>hefA<\/jats:italic> knockout mutants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that <jats:italic>rdxA<\/jats:italic> mutations play a critical role in metronidazole resistance as well as the outcomes of eradication therapy. In addition, <jats:italic>hefA<\/jats:italic> seems to be directly involved in metronidazole resistance, which explains the resistance in clinical isolates with intact <jats:italic>rdxA<\/jats:italic> and <jats:italic>frxA<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.13906","type":"journal-article","created":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T06:02:38Z","timestamp":1501135358000},"page":"681-688","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["<i>rdxA, frxA<\/i>, and efflux pump in metronidazole\u2010resistant <i>Helicobacter pylori<\/i>: Their relation to clinical outcomes"],"prefix":"10.1111","volume":"33","author":[{"given":"Sun Min","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital  Seongnam Gyeonggi\u2010do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital  Seongnam Gyeonggi\u2010do Korea"},{"name":"Department of Internal Medicine and Liver Research Institute Seoul National University College of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Hwan","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital  Seongnam Gyeonggi\u2010do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoung Hee","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital  Seongnam Gyeonggi\u2010do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Mogg","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology Hanyang University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Youn","family":"Park","sequence":"additional","affiliation":[{"name":"School of Pharmacy MCPHS University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul National University Bundang Hospital  Seongnam Gyeonggi\u2010do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,2,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1001110"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000085"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i18.5461"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i18.5191"},{"key":"e_1_2_6_6_1","unstructured":"Schistosomes liver flukes andHelicobacter pylori. 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