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For many decades, effective and non-toxic \u03b2-lactam antibiotics have been successfully used as mimetics of the d-Ala-d-Ala moiety of the natural substrate and employed as irreversible inhibitors of PBPs. In the years following their discovery, the emergence of resistant bacteria led to a decline in their clinical efficacy. Using Staudinger cycloaddition, we synthesized a focused library of novel monocyclic \u03b2-lactams in which different substituents were introduced at the C4 position of the \u03b2-lactam ring, at the C3 amino position, and at the N1 lactam nitrogen. In biochemical assays, the compounds were evaluated for their inhibitory effect on the model enzyme PBP1b from\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    . Upon investigation of the antibacterial activity of the newly prepared compounds against ESKAPE pathogens, some compounds showed moderate inhibition. We also examined their reactivity and selectivity in a biochemical assay with other enzymes that have a catalytic serine in the active site, such as human cholinesterases, where they also showed no inhibitory activity, highlighting their specificity for bacterial targets. These compounds form the basis for further work on new monocyclic \u03b2-lactams with improved antibacterial activity.\n                  <\/jats:p>","DOI":"10.2478\/acph-2024-0024","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T04:08:10Z","timestamp":1726459690000},"page":"423-440","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis and biochemical evaluation of new 3-amido-4-substituted monocyclic \u00df-lactams as inhibitors of penicillin-binding protein(s)"],"prefix":"10.2478","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6478-7696","authenticated-orcid":false,"given":"Katarina","family":"Grabrijan","sequence":"first","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nika Stra\u0161ek","family":"Benedik","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7822-1944","authenticated-orcid":false,"given":"Alen","family":"Krajnc","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0025-1734","authenticated-orcid":false,"given":"Kri\u0161tof","family":"Bozovi\u010dar","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Biology, Faculty of Pharmacy , University of Ljubljana , Ljubljana , Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-1384","authenticated-orcid":false,"given":"Damijan","family":"Knez","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4043-9686","authenticated-orcid":false,"given":"Matic","family":"Proj","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5419-2779","authenticated-orcid":false,"given":"Irena","family":"Zdovc","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Parasitology , Veterinary Faculty University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3370-4587","authenticated-orcid":false,"given":"Izidor","family":"Sosi\u010d","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1151-5766","authenticated-orcid":false,"given":"Carlos","family":"Contreras-Martel","sequence":"additional","affiliation":[{"name":"University Grenoble Alpes, CNRS CEA, Institut de Biologie Structurale (IBS), Bacterial Pathogenesis Group Grenoble , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6487-4020","authenticated-orcid":false,"given":"Andr\u00e9a","family":"Dessen","sequence":"additional","affiliation":[{"name":"University Grenoble Alpes, CNRS CEA, Institut de Biologie Structurale (IBS), Bacterial Pathogenesis Group Grenoble , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-2445","authenticated-orcid":false,"given":"Martina Hrast","family":"Rambaher","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-3083","authenticated-orcid":false,"given":"Stanislav","family":"Gobec","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana , Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"2026061223583217845_j_acph-2024-0024_ref_001","doi-asserted-by":"crossref","unstructured":"C. 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