{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:19:54Z","timestamp":1787026794240,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"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>\n                    In this study, we investigated the\n                    <jats:italic>in vitro<\/jats:italic>\n                    activity and resistance mechanisms of the new generation tetracycline agents, namely eravacycline, omadacycline, and tigecycline, against\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    isolates. A total of 1,017 non-duplicate\n                    <jats:italic>S. aureus<\/jats:italic>\n                    isolates were collected and subjected to susceptibility testing against eravacycline, omadacycline, and tigecycline using the broth microdilution method. Tetracyclines-resistant (eravacycline\/omadacycline\/tigecycline-resistant) isolates were selected to elucidate the resistance mechanisms using polymerase chain reaction (PCR), cloning experiment, efflux pump inhibition, and quantitative real-time PCR. The results of the antibacterial susceptibility testing showed that compared with omadacycline, eravacycline and tigecycline had superior antibacterial activity against\n                    <jats:italic>S. aureus<\/jats:italic>\n                    isolates. Among 1,017\n                    <jats:italic>S. aureus<\/jats:italic>\n                    , 41 tetracyclines-resistant isolates were identified. These resistant isolates possessed at least one tetracycline resistance gene and genetic mutation in the MepRAB efflux pump and 30S ribosome units. A frameshift mutation in\n                    <jats:italic>mepB<\/jats:italic>\n                    was detected in most tetracyclines-resistant strains (except for JP3349) compared with tetracyclines-susceptible (eravacycline\/omadacycline\/tigecycline-susceptible) strains. This was first shown to decrease susceptibility to omadacycline, but not to eravacycline and tigecycline. After treatment with eravacycline, omadacycline or tigecycline, overexpression of\n                    <jats:italic>mepA<\/jats:italic>\n                    ,\n                    <jats:italic>tet38<\/jats:italic>\n                    ,\n                    <jats:italic>tet<\/jats:italic>\n                    (K) and\n                    <jats:italic>tet<\/jats:italic>\n                    (L) was detected. Moreover, multi-locus sequence typing showed a major clonal dissemination type, ST5, and its variant ST764 were seen in most tetracyclines-resistant strains. To conclude, eravacycline and tigecycline exhibited better activity against\n                    <jats:italic>S. aureus<\/jats:italic>\n                    including tetracycline-resistant isolates than omadacycline. The resistance to these new generation tetracyclines due to an accumulation of many resistance mechanisms.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2022.1043736","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T23:40:41Z","timestamp":1669074041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["In vitro antimicrobial activity and resistance mechanisms of the new generation tetracycline agents, eravacycline, omadacycline, and tigecycline against clinical Staphylococcus aureus isolates"],"prefix":"10.3389","volume":"13","author":[{"given":"Weiliang","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sipei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tieli","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1002\/pro.2438","article-title":"Structural characterization of MepB from Staphylococcus aureus reveals homology to endonucleases","volume":"23","author":"Agah","year":"2014","journal-title":"Protein Sci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.3389\/fmicb.2019.02546","article-title":"In vitro activity and Heteroresistance of omadacycline against clinical Staphylococcus aureus isolates from China reveal the impact of omadacycline susceptibility by branched-chain amino acid transport system II carrier protein, Na\/pi cotransporter family protein, and fibronectin-binding protein","volume":"10","author":"Bai","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"5561","DOI":"10.1128\/aac.00547-15","article-title":"The ribosomal S10 protein is a general target for decreased tigecycline susceptibility","volume":"59","author":"Beabout","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"106215","DOI":"10.1016\/j.ijantimicag.2020.106215","article-title":"In vitro activity of eravacycline and mechanisms of resistance in enterococci","volume":"56","author":"Boukthir","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1093\/jac\/dkx432","article-title":"Effect of Staphylococcus aureus Tet38 native efflux pump on in vivo response to tetracycline in a murine subcutaneous abscess model","volume":"73","author":"Chen","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1007\/s12223-020-00816-2","article-title":"RamA, a transcriptional regulator conferring florfenicol resistance in Leclercia adecarboxylata R25","volume":"65","author":"Cheng","year":"2020","journal-title":"Folia Microbiol. (Praha)"},{"key":"ref7","first-page":"M100","volume-title":"Performance Standards for Antimicrobial Susceptibility Testing","year":"2022"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1089\/mdr.2017.0279","article-title":"Resistance in in vitro selected tigecycline-resistant methicillin-resistant Staphylococcus aureus sequence type 5 is driven by mutations in mep R and mepA genes","volume":"24","author":"Dabul","year":"2018","journal-title":"Microb. Drug Resist."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1016\/j.clinthera.2006.08.011","article-title":"Tigecycline: a glycylcycline antimicrobial agent","volume":"28","author":"Doan","year":"2006","journal-title":"Clin. Ther."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.jgar.2018.11.007","article-title":"Antimicrobial susceptibility of gram-negative and gram-positive bacteria collected from eastern Europe: results from the tigecycline evaluation and surveillance trial (T.E.S.T.), 2011-2016","volume":"17","author":"Dowzicky","year":"2019","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.jgar.2020.06.005","article-title":"Mutations in the MepRAB efflux system contribute to the in vitro development of tigecycline resistance in Staphylococcus aureus","volume":"22","author":"Fang","year":"2020","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref12","year":"2020"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1093\/jac\/dkv420","article-title":"Tigecycline resistance in clinical isolates of enterococcus faecium is mediated by an upregulation of plasmid-encoded tetracycline determinants tet(L) and tet(M)","volume":"71","author":"Fiedler","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1093\/jac\/dkt396","article-title":"Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin","volume":"69","author":"Gasch","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"a025387","DOI":"10.1101\/cshperspect.a025387","article-title":"Tetracycline antibiotics and resistance","volume":"6","author":"Grossman","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1093\/cid\/ciy739","article-title":"A prognostic model of persistent bacteremia and mortality in complicated Staphylococcus aureus bloodstream infection","volume":"68","author":"Guimaraes","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.3389\/fmicb.2018.02078","article-title":"Single nucleotide polymorphism analysis indicates genetic distinction and reduced diversity of swine-associated methicillin resistant Staphylococcus aureus (MRSA) ST5 isolates compared to clinical MRSA ST5 isolates","volume":"9","author":"Hau","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1080\/22221751.2020.1868950","article-title":"Increasing prevalence of hypervirulent ST5 methicillin susceptible Staphylococcus aureus subtype poses a serious clinical threat","volume":"10","author":"Jian","year":"2021","journal-title":"Emerg. Microbes. Infect."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"7636983","DOI":"10.1155\/2022\/7636983","article-title":"Omadacycline efficacy against Streptococcus agalactiae isolated in China: correlation between resistance and virulence gene and Biofilm formation","volume":"2022","author":"Li","year":"2022","journal-title":"Comput. Intell. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"104502","DOI":"10.1016\/j.micpath.2020.104502","article-title":"Comparison of antimicrobial efficacy of eravacycline and tigecycline against clinical isolates of Streptococcus agalactiae in China: in vitro activity, heteroresistance, and cross-resistance","volume":"149","author":"Li","year":"2020","journal-title":"Microb. Pathog."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.jgar.2022.06.014","article-title":"Comparing core-genome MLST with PFGE and MLST for cluster analysis of carbapenem-resistant Acinetobacter baumannii","volume":"30","author":"Li","year":"2022","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1128\/aac.02465-15","article-title":"Potential of tetracycline resistance proteins to evolve tigecycline resistance","volume":"60","author":"Linkevicius","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"3140","DOI":"10.1073\/pnas.95.6.3140","article-title":"Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms","volume":"95","author":"Maiden","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1128\/aac.49.5.1865-1871.2005","article-title":"A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline","volume":"49","author":"McAleese","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref25","first-page":"269","article-title":"Vancomycin resistance in Staphylococcus aureus","volume":"90","author":"McGuinness","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e01715-15","DOI":"10.1128\/aac.01715-19","article-title":"In vitro activity of eravacycline against gram-positive bacteria isolated in clinical laboratories worldwide from 2013 to 2017","volume":"64","author":"Morrissey","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1515\/hsz-2013-0292","article-title":"Tetracycline antibiotics and resistance mechanisms","volume":"395","author":"Nguyen","year":"2014","journal-title":"Biol. Chem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"S303","DOI":"10.1086\/431672","article-title":"Tigecycline: a new glycylcycline for treatment of serious infections","volume":"41","author":"Noskin","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.3389\/fmicb.2018.02210","article-title":"Molecular epidemiology of Staphylococcus aureus bacteremia: association of molecular factors with the source of infection","volume":"9","author":"P\u00e9rez-Montarelo","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1086\/367622","article-title":"Tetracycline therapy: update","volume":"36","author":"Roberts","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.femsle.2005.02.034","article-title":"Update on acquired tetracycline resistance genes","volume":"245","author":"Roberts","year":"2005","journal-title":"FEMS Microbiol. Lett."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"647060","DOI":"10.3389\/fphar.2021.647060","article-title":"From genome to drugs: new approaches in antimicrobial discovery","volume":"12","author":"Serral","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.2217\/fmb-2019-0135","article-title":"Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance","volume":"14","author":"Solomkin","year":"2019","journal-title":"Future Microbiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1128\/aac.01147-12","article-title":"A new local variant (ST764) of the globally disseminated ST5 lineage of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) carrying the virulence determinants of community-associated MRSA","volume":"57","author":"Takano","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"4362","DOI":"10.1128\/iai.00723-15","article-title":"Role of the Tet38 efflux pump in Staphylococcus aureus internalization and survival in epithelial cells","volume":"83","author":"Truong-Bolduc","year":"2015","journal-title":"Infect. Immun."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e0131021","DOI":"10.1128\/Spectrum.01310-21","article-title":"Novel Tet (L) efflux pump variants conferring resistance to tigecycline and eravacycline in Staphylococcus Spp","volume":"9","author":"Wang","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s12866-020-01869-6","article-title":"Eravacycline susceptibility was impacted by genetic mutation of 30S ribosome subunits, and branched-chain amino acid transport system II carrier protein, Na\/pi cotransporter family protein in Staphylococcus aureus","volume":"20","author":"Wang","year":"2020","journal-title":"BMC Microbiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1186\/s12866-020-02019-8","article-title":"Antimicrobial activity of omadacycline in vitro against bacteria isolated from 2014 to 2017 in China, a multi-center study","volume":"20","author":"Xiao","year":"2020","journal-title":"BMC Microbiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.3389\/fmicb.2020.01290","article-title":"Molecular mechanisms and epidemiology of Fosfomycin resistance in Staphylococcus aureus isolated from patients at a teaching hospital in China","volume":"11","author":"Xu","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.diagmicrobio.2017.12.013","article-title":"In vitro activity of eravacycline against 2213 gram-negative and 2424 gram-positive bacterial pathogens isolated in Canadian hospital laboratories: CANWARD surveillance study 2014-2015","volume":"91","author":"Zhanel","year":"2018","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s40265-016-0545-8","article-title":"Review of eravacycline, a novel fluorocycline antibacterial agent","volume":"76","author":"Zhanel","year":"2016","journal-title":"Drugs"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s40265-020-01257-4","article-title":"Omadacycline: a novel oral and intravenous aminomethylcycline antibiotic agent","volume":"80","author":"Zhanel","year":"2020","journal-title":"Drugs"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s12866-018-1349-7","article-title":"Eravacycline activity against clinical S. aureus isolates from China: in vitro activity, MLST profiles and heteroresistance","volume":"18","author":"Zhang","year":"2018","journal-title":"BMC Microbiol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1186\/s12879-019-4093-1","article-title":"In vitro activities of eravacycline against 336 isolates collected from 2012 to 2016 from 11 teaching hospitals in China","volume":"19","author":"Zhao","year":"2019","journal-title":"BMC Infect. Dis."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1093\/jac\/dkaa485","article-title":"Identification of a novel tetracycline resistance gene, tet(63), located on a multiresistance plasmid from Staphylococcus aureus","volume":"76","author":"Zhu","year":"2021","journal-title":"J. Antimicrob. Chemother."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1043736\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T23:40:45Z","timestamp":1669074045000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1043736\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,22]]},"references-count":45,"alternative-id":["10.3389\/fmicb.2022.1043736"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.1043736","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,22]]},"article-number":"1043736"}}