{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T15:19:06Z","timestamp":1786202346861,"version":"build-2736575974"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oral Health"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Periodontitis, a chronic inflammatory disease affecting the periodontium, is primarily driven by dysbiosis of the oral microbiome with\n                      <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                      as a keystone pathogen. Current therapeutic approaches rely on mechanical debridement and antimicrobials, which face limitations including antibiotic resistance and microbiome disruption. Pathoblockers represent a novel therapeutic strategy that selectively targets virulence factors without bactericidal effects, potentially reducing resistance development while preserving beneficial microbiota. Here, we describe the characterization of S-0636, a novel reversible inhibitor of zinc-dependent glutaminyl cyclase (PgQC), as a compound to selectively inhibit the bacterial virulence of\n                      <jats:italic>P. gingivalis<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The compound's effects were assessed through enzymatic assays, bacterial growth studies, virulence factor activity measurements (gingipain activity, hemagglutination, keratinocyte invasion), selectivity testing against commensal oral bacteria, resistance development analysis over 50 passages, and cytotoxicity evaluation in human cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      S-0636 demonstrated potent PgQC inhibition with a K\n                      <jats:sub>i<\/jats:sub>\n                      value of 0.014\u2005\u03bcM and has successfully reduced the intracellular PgQC activity by 50% at 8\u2005\u03bcM and had no bactericidal effects. Treatment of\n                      <jats:italic>P. gingivalis<\/jats:italic>\n                      with S-0636 significantly decreased gingipain activity, impaired hemagglutination capacity, and reduced keratinocyte invasion by 76% at 62.5\u2005\u03bcM. The compound showed high selectivity, with no growth inhibition of ten tested oral commensal species at concentrations up to 0.25\u2005mM. Importantly, no resistance development was observed after 50 bacterial passages, and cytotoxicity remained minimal in human cell lines with &amp;gt;80% viability at 0.5\u2005mM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      In previous studies, PgQC was suggested as an enzyme responsible for pGlu-modification and stabilization of bacterial virulence factors. The current study now validates PgQC as an attractive target for pathoblocker development, demonstrating that S-0636 effectively attenuates\n                      <jats:italic>P. gingivalis<\/jats:italic>\n                      pathogenicity through selective virulence factor inhibition while preserving bacterial viability and oral microbiome integrity. The absence of resistance development and low cytotoxicity profile support the potential clinical translation of this approach for periodontal disease management, representing a promising alternative to conventional antimicrobial therapies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/froh.2026.1716188","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:47:19Z","timestamp":1773384439000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel small molecule targeting PgQC reduces Porphyromonas gingivalis virulence"],"prefix":"10.3389","volume":"7","author":[{"given":"Nadine","family":"Taudte","sequence":"first","affiliation":[{"name":"Periotrap Pharmaceuticals GmbH","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Liebe","sequence":"additional","affiliation":[{"name":"Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"J\u00e4nckel","sequence":"additional","affiliation":[{"name":"Periotrap Pharmaceuticals GmbH","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ramsbeck","sequence":"additional","affiliation":[{"name":"Periotrap Pharmaceuticals GmbH","place":["Halle (Saale), Germany"]},{"name":"Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schilling","sequence":"additional","affiliation":[{"name":"Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Potempa","sequence":"additional","affiliation":[{"name":"Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry","place":["Louisville, KY, United States"]},{"name":"Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun","family":"Eick","sequence":"additional","affiliation":[{"name":"Department of Periodontology, School of Dental Medicine, University of Bern","place":["Bern, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Buchholz","sequence":"additional","affiliation":[{"name":"Periotrap Pharmaceuticals GmbH","place":["Halle (Saale), Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat Pub Group"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5231","DOI":"10.3390\/ijms24065231","article-title":"The role of the oral microbiome in the development of diseases","volume":"24","author":"Kozak","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2197779","DOI":"10.1080\/20002297.2023.2197779","article-title":"Current concepts in the pathogenesis of periodontitis: from symbiosis to dysbiosis","volume":"15","author":"Abdulkareem","year":"2023","journal-title":"J Oral Microbiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1016\/j.csbj.2021.02.010","article-title":"The oralome and its dysbiosis: new insights into oral microbiome-host interactions","volume":"19","author":"Radaic","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"B5","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/jcpe.12420","article-title":"Prevalence of periodontitis in an adult population from an urban area in north Italy: findings from a cross-sectional population-based epidemiological survey","volume":"42","author":"Aimetti","year":"2015","journal-title":"J Clin Periodontol"},{"key":"B6","volume-title":"Mundgesundheit (No. Heft 47), Gesundheitsberichterstattung des Bundes","author":"Brauckhoff","year":"2009"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.it.2013.09.001","article-title":"Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response","volume":"35","author":"Hajishengallis","year":"2014","journal-title":"Trends Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/nrmicro2873","article-title":"The keystone-pathogen hypothesis. 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