{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:46:49Z","timestamp":1792025209284,"version":"4.4.0"},"reference-count":22,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Bacterial sexually transmitted infections (STIs) pose a major public health problem. The emergence of antibiotic-resistant strains of <jats:italic>Neisseria gonorrhoeae<\/jats:italic> represents a serious threat to successful treatment and epidemiological control. The first extensively drug-resistant (XDR) strains (ceftriaxone-resistant and high-level azithromycin-resistant [HLR AZY]) have been reported.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Aims<\/jats:title>\n<jats:p>To identify molecular mechanisms implicated in azithromycin resistance in strains isolated from patients over a three-year period in a university hospital in Switzerland.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Material and methods<\/jats:title>\n<jats:p>From January 2020 to December 2022, 34 isolates (one per patient) were recovered from samples analyzed at the University Hospital of Lausanne. Eight genes involved in azithromycin resistance were sequenced: <jats:italic>mtrR<\/jats:italic> repressor (mtrCDE operon repressor) and his promotor <jats:italic>mtrR-pr<\/jats:italic>, <jats:italic>rplD<\/jats:italic> gene (L4 ribosomal protein), <jats:italic>rplV<\/jats:italic> gene (L22 ribosomal protein) and the four alleles of the <jats:italic>rrl<\/jats:italic> gene (23S rRNA).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>With a cutoff value of 1 mg\/L, 15 isolates were considered as being resistant to azithromycin, whereas the remaining 19 were susceptible. The C2597T mutation in 3 or 4 of the <jats:italic>rrl<\/jats:italic> allele confer a medium-level resistance to azithromycin (MIC = 16 mg\/L, N = 2). The following mutations were significantly associated with MIC values \u22651 mg\/L: the three mutations V125A, A147G, R157Q in the <jats:italic>rplD<\/jats:italic> gene (N = 10) and a substitution A-&gt;C in the <jats:italic>mtrR<\/jats:italic> promotor (N = 9). Specific mutations in the <jats:italic>mtrR<\/jats:italic> repressor and its promotor were observed in both susceptible and resistant isolates.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Resistance to azithromycin was explained by the presence of mutations in many different copies of 23S RNA ribosomal genes and their regulatory genes. Other mutations, previously reported to be associated with azithromycin resistance, were documented in both susceptible and resistant isolates, suggesting they play little role, if any, in azithromycin resistance.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0306695","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T17:28:14Z","timestamp":1721150894000},"page":"e0306695","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Impact of mutations in the mtrR, rpdlVD and rrl genes on azithromycin resistance in Neisseria gonorrhoeae"],"prefix":"10.1371","volume":"19","author":[{"given":"Florian","family":"Mauffrey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Poncet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Jacot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Greub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Nordmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0324-8437","authenticated-orcid":true,"given":"Dominique S.","family":"Blanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"pone.0306695.ref001","author":"M. Jacobsson SU","year":"2018","journal-title":"Gonococcal antimicrobial susceptibility surveillance in Europe\u2014Technical document"},{"key":"pone.0306695.ref002","author":"WHO","year":"2016","journal-title":"New guidelines for chlamydia, gonorrhoea and syphilis."},{"key":"pone.0306695.ref003","author":"eCDC","year":"2018","journal-title":"Extensively drug-resistant (XDR) Neisseria gonorrhoeae in the United Kingdom and Australia"},{"issue":"1","key":"pone.0306695.ref004","first-page":"29","article-title":"Increasing prevalence of Neisseria gonorrhoeae with decreased susceptibility to ceftriaxone and resistance to azithromycin in Hangzhou, China (2015\u201317).","volume":"74","author":"J Yan","year":"2019","journal-title":"J Antimicrob Chemother"},{"issue":"9","key":"pone.0306695.ref005","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1128\/AAC.00309-10","article-title":"High-level azithromycin resistance occurs in Neisseria gonorrhoeae as a result of a single point mutation in the 23S rRNA genes","volume":"54","author":"SA Chisholm","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"issue":"4","key":"pone.0306695.ref006","article-title":"Emergence of Neisseria gonorrhoeae Strains Harboring a Novel Combination of Azithromycin-Attenuating Mutations","volume":"63","author":"CD Pham","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pone.0306695.ref007","doi-asserted-by":"crossref","first-page":"188","DOI":"10.3390\/antibiotics4020188","article-title":"The Transcriptional Repressor, MtrR, of the mtrCDE Efflux Pump Operon of Neisseria gonorrhoeae Can Also Serve as an Activator of \"off Target\" Gene (glnE) Expression.","volume":"4","author":"PJ Johnson","year":"2015","journal-title":"Antibiotics (Basel)."},{"issue":"4","key":"pone.0306695.ref008","article-title":"Efflux Pump Antibiotic Binding Site Mutations Are Associated with Azithromycin Nonsusceptibility in Clinical Neisseria gonorrhoeae Isolates.","volume":"11","author":"KC Ma","year":"2020","journal-title":"mBio"},{"issue":"5","key":"pone.0306695.ref009","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00187-11","article-title":"A novel mechanism of high-level, broad-spectrum antibiotic resistance caused by a single base pair change in Neisseria gonorrhoeae.","volume":"2","author":"EA Ohneck","year":"2011","journal-title":"mBio"},{"issue":"6","key":"pone.0306695.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02281-18","article-title":"Mechanistic Basis for Decreased Antimicrobial Susceptibility in a Clinical Isolate of Neisseria gonorrhoeae Possessing a Mosaic-Like mtr Efflux Pump Locus.","volume":"9","author":"CE Rouquette-Loughlin","year":"2018","journal-title":"mBio"},{"issue":"5","key":"pone.0306695.ref011","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01747-18","article-title":"Mosaic Drug Efflux Gene Sequences from Commensal Neisseria Can Lead to Low-Level Azithromycin Resistance Expressed by Neisseria gonorrhoeae Clinical Isolates","volume":"9","author":"WM Shafer","year":"2018","journal-title":"mBio"},{"issue":"4","key":"pone.0306695.ref012","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01419-18","article-title":"Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in Neisseria gonorrhoeae.","volume":"9","author":"CB Wadsworth","year":"2018","journal-title":"mBio"},{"issue":"9","key":"pone.0306695.ref013","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1093\/jac\/dkw182","article-title":"Molecular epidemiology and mechanisms of resistance of azithromycin-resistant Neisseria gonorrhoeae isolated in France during 2013\u201314","volume":"71","author":"A Belkacem","year":"2016","journal-title":"J Antimicrob Chemother"},{"issue":"9","key":"pone.0306695.ref014","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1007\/s10096-018-3296-5","article-title":"Antimicrobial resistance and molecular epidemiology using whole-genome sequencing of Neisseria gonorrhoeae in Ireland, 2014\u20132016: focus on extended-spectrum cephalosporins and azithromycin","volume":"37","author":"L Ryan","year":"2018","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"6","key":"pone.0306695.ref015","doi-asserted-by":"crossref","first-page":"e452","DOI":"10.1016\/S2666-5247(22)00044-1","article-title":"Europe-wide expansion and eradication of multidrug-resistant Neisseria gonorrhoeae lineages: a genomic surveillance study","volume":"3","author":"L Sanchez-Buso","year":"2022","journal-title":"Lancet Microbe"},{"issue":"6","key":"pone.0306695.ref016","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1128\/AAC.01420-07","article-title":"Relation between genetic markers of drug resistance and susceptibility profile of clinical Neisseria gonorrhoeae strains","volume":"52","author":"EN Ilina","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pone.0306695.ref017","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1128\/AAC.00788-10","article-title":"Molecular analysis of antimicrobial resistance mechanisms in Neisseria gonorrhoeae isolates from Ontario, Canada","volume":"55","author":"VG Allen","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"pone.0306695.ref018","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1128\/CMR.00010-14","article-title":"Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.","volume":"27","author":"M Unemo","year":"2014","journal-title":"Clin Microbiol Rev."},{"issue":"11","key":"pone.0306695.ref019","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1093\/jac\/dkw288","article-title":"The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization","volume":"71","author":"M Unemo","year":"2016","journal-title":"J Antimicrob Chemother"},{"issue":"1","key":"pone.0306695.ref020","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.1038\/s41467-020-19250-6","article-title":"Increased power from conditional bacterial genome-wide association identifies macrolide resistance mutations in Neisseria gonorrhoeae.","volume":"11","author":"KC Ma","year":"2020","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0306695.ref021","doi-asserted-by":"crossref","first-page":"e0168821","DOI":"10.1128\/aac.01688-21","article-title":"Increasing Azithromycin Resistance in Neisseria gonorrhoeae Due to NG-MAST 12302 Clonal Spread in Canada, 2015 to 2018","volume":"66","author":"P Sawatzky","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"issue":"11","key":"pone.0306695.ref022","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1093\/jac\/dkw279","article-title":"WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg\/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014.","volume":"71","author":"S Jacobsson","year":"2016","journal-title":"J Antimicrob Chemother"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0306695","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T17:28:30Z","timestamp":1721150910000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0306695"}},"subtitle":[],"editor":[{"given":"Mohamed O.","family":"Ahmed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":22,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0306695","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,16]]}}}