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Motivated by the pressing need for new anti\u2010infective therapies caused by antimicrobial resistance, inhibitors of LecA are under investigation. Complementary to the use of carbohydrate\u2010based inhibitors, we have previously identified catechols as weak but specific ligands of LecA, constituting a novel class of non\u2010carbohydrate glycomimetics. By growing the initial millimolar fragment hits, we identified Tolcapone as a promising compound. To gain insight into the structure\u2010activity relationship (SAR) of catechols as LecA binders, more than 3,200 compounds of the Roche in\u2010house library were experimentally screened in a competitive binding assay at three concentrations. Of these, 48 compounds were chosen for further investigation, resulting in compounds equipotent to aryl galactosides, the current epitome of LecA inhibition. X\u2010ray crystallography and saturation transfer difference (STD) NMR spectroscopy revealed conserved interactions of the catechol moiety in the glycan binding site of LecA and rationalized the observed SAR. Our findings demonstrate that it is possible to develop potent non\u2010carbohydrate glycomimetic lectin inhibitors. This work paves the way for a new avenue of research towards innovative anti\u2010infective drugs. In a more general perspective, such small molecules also hold potential to challenge the hegemony of antibodies for lectin inhibition in clinical use.\n                  <\/jats:p>","DOI":"10.1002\/anie.202508864","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T07:11:36Z","timestamp":1762153896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Parkinson's Disease Drug Tolcapone and Analogues are Potent Glycomimetic Lectin Inhibitors of\n                    <i>Pseudomonas aeruginosa<\/i>\n                    LecA"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4342-5749","authenticated-orcid":false,"given":"Steffen","family":"Leusmann","sequence":"first","affiliation":[{"name":"Chemical Biology of Carbohydrates (CBCH) Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research  66123 Saarbr\u00fccken Germany"},{"name":"Department of Chemistry PharmaScienceHub (PSH), Saarland University  66123 Saarbr\u00fccken Germany"},{"name":"Deutsches Zentrum f\u00fcr Infektionsforschung (DZIF), Standort Hannover\u2010Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-9872","authenticated-orcid":false,"given":"Eike","family":"Siebs","sequence":"additional","affiliation":[{"name":"Chemical Biology of Carbohydrates (CBCH) Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research  66123 Saarbr\u00fccken Germany"},{"name":"Department of Chemistry PharmaScienceHub (PSH), Saarland University  66123 Saarbr\u00fccken Germany"},{"name":"Deutsches Zentrum f\u00fcr Infektionsforschung (DZIF), Standort Hannover\u2010Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-3781","authenticated-orcid":false,"given":"Sakonwan","family":"Kuhaudomlarp","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromol\u00e9cules V\u00e9g\u00e9tales (CERMAV)  Grenoble 38000 France"},{"name":"Department of Biochemistry Faculty of Science Mahidol University  Bangkok 10400 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6667-8162","authenticated-orcid":false,"given":"Annabelle","family":"Varrot","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromol\u00e9cules V\u00e9g\u00e9tales (CERMAV)  Grenoble 38000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6825-9527","authenticated-orcid":false,"given":"Anne","family":"Imberty","sequence":"additional","affiliation":[{"name":"Univ. 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