{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:37:13Z","timestamp":1791110233245,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>With the widespread use and abuse of antibiotics, <jats:italic>Helicobacter pylori<\/jats:italic> (<jats:italic>H. pylori<\/jats:italic>) has become seriously drug resistant. The development of new antibiotics is an important way to solve <jats:italic>H. pylori<\/jats:italic>'s drug resistance. Screening antibacterial ingredients from natural products is a convenient way to develop new antibiotics. Phillygenin, an effective antibacterial component, was selected from the natural product, forsythia, in this study. Its minimal inhibitory concentration (MIC) for 18 <jats:italic>H. pylori<\/jats:italic> strains was 16\u201332 \u03bcg\/ml. The minimum bactericidal concentration (MBC) of <jats:italic>H. pylori<\/jats:italic> G27 was 128 \u03bcg\/ml; the higher the drug concentration and the longer the time, the better the sterilization effect. It was non-toxic to gastric epithelial cell (GES)-1 and BGC823 cells at the concentration of 100 \u03bcg\/ml. It presented a better antibacterial effect on <jats:italic>H. pylori<\/jats:italic> in an acidic environment, and after 24 days of induction on <jats:italic>H. pylori<\/jats:italic> with 1\/4 MIC of phillygenin, no change was found in the MIC of <jats:italic>H. pylori<\/jats:italic>. In the mechanism of action, phillygenin could cause ATP leakage and inhibit the biofilm formation; the latter was associated with the regulation of <jats:italic>spoT<\/jats:italic> and <jats:italic>Hp1174<\/jats:italic> genes. In addition, phillygenin could regulate the genes of <jats:italic>Nhac, caggamma, MATE, MdoB, flagellinA<\/jats:italic>, and <jats:italic>lptB<\/jats:italic>, leading to the weakening of <jats:italic>H. pylori<\/jats:italic>'s acid resistance and virulence, the diminishing of <jats:italic>H. pylori<\/jats:italic>'s capacity for drug efflux, <jats:italic>H. pylori<\/jats:italic>'s DNA methylation, the initiation of human immune response, and the ATP leakage of <jats:italic>H. pylori<\/jats:italic>, thus accelerating the death of <jats:italic>H. pylori<\/jats:italic>. In conclusion, phillygenin was a main ingredient inhibiting <jats:italic>H. pylori<\/jats:italic> in <jats:italic>Forsythia suspensa<\/jats:italic>, with a good antibacterial activity, high safety, strong specificity, better antibacterial effect under acidic conditions, and low risk of resistance development by <jats:italic>H. pylori<\/jats:italic>. Its mechanism of action was mainly associated with inhibiting the biofilm formation and resulting in ATP leakage. In addition, phillygenin was shown to be able to reduce the acid resistance and virulence of <jats:italic>H. pylori<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fmicb.2022.863624","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T17:37:08Z","timestamp":1651167428000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Phillygenin Inhibits Helicobacter pylori by Preventing Biofilm Formation and Inducing ATP Leakage"],"prefix":"10.3389","volume":"13","author":[{"given":"Ru-Jia","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gan-Rong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Juan","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qiang","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Qiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1053\/j.gastro.2010.10.033","article-title":"A national study of Helicobactor pylori infection in gastric biopsy specimens","volume":"139","author":"Amnon","year":"2010","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6474","DOI":"10.1038\/s41598-019-42876-6","article-title":"Fragment-based screening identifies inhibitors of ATPase activity and of hexamer formation of Cag\u03b1 from the Helicobacter pylori type IV secretion system","volume":"9","author":"Arya","year":"2019","journal-title":"Sci Rep"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023479","article-title":"The RelA\/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life","author":"Atkinson","year":"2011","journal-title":"PLoS ONE"},{"key":"B4","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1111\/jam.14800","article-title":"Antimicrobial effects of three herbs (Brassica juncea, Forsythia suspensa, and Inula britannica) on membrane permeability and apoptosis in Salmonella","volume":"130","author":"Bae","year":"2020","journal-title":"J. Appl. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.3748\/wjg.v23.i7.1163","article-title":"Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics","volume":"23","author":"Bahareh","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1111\/j.1365-2958.2004.04137.x","article-title":"Responsiveness to acidity via metal ion regulators mediates virulence in the gastric pathogen Helicobacter pylori","volume":"53","author":"Bury-Mon\u00e9","year":"2004","journal-title":"Mol. Microbiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"12715","DOI":"10.1111\/hel.12715","article-title":"Transporters HP0939, HP0497, and HP0471 participate in intrinsic multidrug resistance and biofilm formation in Helicobacter pylori by enhancing drug efflux","volume":"25","author":"Cai","year":"2020","journal-title":"Helicobacter"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1128\/AAC.45.6.1761-1770.2001","article-title":"Multidrug efflux pumps: expression patterns and contribution to antibiotic resistance in Pseudomonas aeruginosa biofilms","volume":"45","author":"De-Kievit","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"B9","first-page":"80","article-title":"The effect of Shengdi Lianqiao Recipe in controlling dental plaque on the clearance of Helicobacter pylori in patients with gastritis","volume":"34","author":"Dong","year":"2016","journal-title":"Sichuan Tradit. Chin. Med."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00957-18","article-title":"Bifunctional enzyme SpoT is involved in biofilm formation of Helicobacter pylori with multidrug resistance by upregulating efflux pump Hp1174 (gluP)","author":"Ge","year":"2018","journal-title":"Antimicrob. Agents Chemother"},{"key":"B11","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41522-020-00167-3","article-title":"Genetic requirements and transcriptomics of Helicobacter pylori biofilm formation on abiotic and biotic surfaces","volume":"6","author":"Hathroubi","year":"2020","journal-title":"NPJ Biofilms Microb."},{"key":"B12","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1089\/mdr.2016.0087","article-title":"Biofilms: microbial shelters against antibiotics","volume":"23","author":"Hathroubi","year":"2017","journal-title":"Microb Drug Resist"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e00001","DOI":"10.1128\/MMBR.00001-18","article-title":"Helicobacter pylori biofilm formation and its potential role in pathogenesis","volume":"82","author":"Hathroubi","year":"2018","journal-title":"Microbiol. Mol. Biol. Rev"},{"key":"B14","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1053\/j.gastro.2017.04.022","article-title":"Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis","volume":"153","author":"Hooi","year":"2017","journal-title":"Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e00004","DOI":"10.1128\/AAC.00004-19","article-title":"In vitro and In vivo activities of zinc linolenate, a selective antibacterial agent against Helicobacter pylori","volume":"63","author":"Huang","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.3390\/pathogens10081033","article-title":"Antibiofilm and antimicrobial-enhancing activity of Chelidonium majus and Corydalis cheilanthifolia extracts against multidrug-resistant Helicobacter pylori","volume":"10","author":"Krzyzek","year":"2021","journal-title":"Pathogens"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.3390\/pathogens9121062","article-title":"Biofilm formation as a complex result of virulence and adaptive responses of Helicobacter pylori","volume":"9","author":"Krzyzek","year":"2020","journal-title":"Pathogens"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-017-1034-2","article-title":"Site-specific His\/Asp phosphoproteomic analysis of prokaryotes reveals putative targets for drug resistance","author":"Lai","year":"2017","journal-title":"BMC Microbiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajg.2021.05.017","article-title":"Genotyping Helicobacter pylori antibiotic resistance and virulence-associated genes in patients with gastric cancer in Wenzhou, China","volume":"22","author":"Li","year":"2021","journal-title":"Arab. J. Gastroenterol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/hel.12475","article-title":"Chinese society of gastroenterology, Chinese study group on Helicobacter pylori and peptic ulcer. Fifth Chinese National Consensus Report on the management of Helicobacter pylori infection","author":"Liu","year":"2018","journal-title":"Helicobacter"},{"key":"B21","doi-asserted-by":"publisher","first-page":"115328","DOI":"10.1016\/j.taap.2020.115328","article-title":"Corrigendum to \u201cForsythoside A inhibits adhesion and migration of monocytes to type II alveolar epithelial cells in lipopolysaccharide-induced acute lung injury through upregulating miR-124\u201d [TOXICOL APPL PHARM 407 (2020) 115252]","volume":"409","author":"Lu","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1128\/JB.00329-16","article-title":"Functional interaction between the cytoplasmic ABC protein LptB and the inner membrane LptC protein, components of the lipopolysaccharide transport machinery in Escherichia coli","volume":"198","author":"Martorana","year":"2016","journal-title":"J. Bacteriol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13099-016-0091-7","article-title":"Systematic review of time trends in the prevalence of Helicobacter pylori infection in China and the USA","volume":"8","author":"Nagy","year":"2016","journal-title":"Gut. Pathog."},{"key":"B24","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nrmicro.2016.25","article-title":"Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model","volume":"14","author":"Okuda","year":"2016","journal-title":"Nat. Rev. Microbiol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e609","DOI":"10.1016\/S2214-109X(16)30143-7","article-title":"Global burden of cancers attributable to infections in 2012:a synthetic analysis","volume":"4","author":"Plummer","year":"2016","journal-title":"Lancet Global Health"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.2147\/DMSO.S305092","article-title":"Forsythoside A alleviates high glucose-induced oxidative stress and inflammation in podocytes by inactivating MAPK signaling via MMP12 inhibition","volume":"14","author":"Quan","year":"2021","journal-title":"Diabetes Metab. Synd. Obesity Targets Ther."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/mSystems.00961-21","article-title":"Periodically disturbing the spatial structure of biofilms can affect the production of an essential virulence factor in Pseudomonas aeruginosa","author":"Quinn","year":"2021","journal-title":"mSystems"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00846","article-title":"Potential role of biofilm formation in the development of digestive tract cancer with special reference to Helicobacter pylori infection","author":"Rizzato","year":"2019","journal-title":"Front. Microbiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s12257-008-0272-4","article-title":"Betulinic and oleanolic acids isolated from Forsythia suspensa Vahl inhibit urease activity of Helicobacter pylori","volume":"14","author":"Seung","year":"2009","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"B30","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1128\/JB.01126-06","article-title":"Characterization of lptA and lptB, two essential genes implicated in lipopolysaccharide transport to the outer membrane of Escherichia coli","volume":"189","author":"Sperandeo","year":"2007","journal-title":"J. Bacteriol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1136\/gutjnl-2015-309252","article-title":"Kyoto global consensus report on Helicobacter pylori gastritis","volume":"64","author":"Sugano","year":"2015","journal-title":"Gut"},{"key":"B32","first-page":"269","article-title":"Primary versus secondary immune thrombocytopenia in adults; a comparative analysis of clinical and laboratory attributes in newly diagnosed patients in Southern Pakistan","volume":"71","author":"Sultan","year":"2016","journal-title":"Med. J. Malaysia"},{"key":"B33","first-page":"286","article-title":"Isolation and identification of the chemical components of Forsythia suspense","volume":"31","author":"Sun","year":"2021","journal-title":"Chinese J. Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"B64","DOI":"10.1038\/srep21015","article-title":"Distribution of the type III DNA methyltransferases modA, modB and modD among Neisseria meningitidis genotypes: implications for gene regulation and virulence","volume":"6","author":"Tan","year":"2016","journal-title":"Sci. Rep."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/femsle\/fnv076","article-title":"Helicobacter pylori vesicles carrying CagA localize in the vicinity of cell-cell contacts and induce histone H1 binding to ATP in epithelial cells","author":"Turkina","year":"2015","journal-title":"FEMS Microbiol. Lett"},{"key":"B36","doi-asserted-by":"publisher","first-page":"756924","DOI":"10.3389\/fphar.2021.756924","article-title":"Phillygenin attenuates carbon tetrachloride-induced liver fibrosis via modulating inflammation and gut microbiota","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B37","first-page":"630","article-title":"Heterogenous expression and characterization of cag4 in Helicobacter pylori","volume":"51","author":"Wang","year":"2011","journal-title":"Wei sheng wu xue bao = Acta Microbiol. Sinica"},{"key":"B38","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1002\/smll.202006877","article-title":"Gastric acid powered nanomotors release antibiotics for in vivo treatment of Helicobacter pylori infection","volume":"17","author":"Wu","year":"2021","journal-title":"Small"},{"key":"B39","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3760\/cma.j.issn.0376-2491.2019.04.012","article-title":"Jinghuaweikang capsules combined with Quadruple therapy in the treatment of Helicobacter pylori infection:a multicenter, randomized, controlled, clinical study","volume":"99","author":"Yang","year":"2019","journal-title":"Zhonghua yi xue za zhi."},{"key":"B40","first-page":"164","article-title":"Determination of flavonoids and triterpene acids in forsythia suspensa leaves from Henan and Shanxi Province","volume":"36","author":"Yuan","year":"2015","journal-title":"Food Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"920","DOI":"10.22038\/IJBMS.2017.9115","article-title":"Antigenic and immunogenic evaluation of Helicobacter pylori FlaA epitopes","volume":"20","author":"Zarei","year":"2017","journal-title":"Iran. J. Basic Med. Sci."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.863624\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T17:37:17Z","timestamp":1651167437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.863624\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,28]]},"references-count":41,"alternative-id":["10.3389\/fmicb.2022.863624"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.863624","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,28]]},"article-number":"863624"}}