{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T01:55:29Z","timestamp":1784426129835,"version":"3.55.0"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,6,15]]},"abstract":"<jats:p>As antibiotic resistance continues to rise, the need for new antibacterials is clear. In this context, Gram\u2010negative bacteria pose a specific challenge due to their multiple possible resistance mechanisms and unique outer membrane. Poor outer membrane permeability limits the activity of many antibiotics. This has led to a growing interest in identifying structural features capable of enhancing small molecule antibiotics\u2019 ability to cross the Gram\u2010negative outer membrane. Examples of such approaches include the incorporation of ionisable amines to promote uptake and the attachment of siderophore moieties to exploit bacterial iron\u2010transport systems. Here, we apply these strategies to a newly discovered class of potent DNA gyrase inhibitors known as the isoquinoline sulphonamides, typified by the compound LEI\u2010800, with the aim of enhancing its Gram\u2010negative activity. In doing so, the distal aromatic ring of the LEI\u2010800 scaffold was functionalised with primary amine, guanidine and siderophore moieties. These studies reveal that the introduction of an ionisable amine group is tolerated at selected positions of the LEI\u2010800 scaffold, resulting in an increased antibacterial activity and mitigating membrane permeability barriers.<\/jats:p>","DOI":"10.1002\/cmdc.70339","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:28:51Z","timestamp":1780540131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimisation of a Novel Class of DNA Gyrase Inhibitors to Improve Antibacterial Activity"],"prefix":"10.1002","volume":"21","author":[{"given":"Meg I.","family":"Ferguson","sequence":"first","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cerissa C.","family":"van Walstijn","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladyslav","family":"Lysenko","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta A.","family":"Wilbrink","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Alencar","family":"Araripe","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Photopharmacology and Imaging Groningen Research Institute of Pharmacy (GRIP) Faculty of Science and Engineering  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen M.","family":"Punt","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology Leiden Institute of Chemistry Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"van der Stelt","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology Leiden Institute of Chemistry Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"Jespers","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Photopharmacology and Imaging Groningen Research Institute of Pharmacy (GRIP) Faculty of Science and Engineering  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Innocenti","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel I.","family":"Martin","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(25)00118-5"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2011.44"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112326"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01738"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.4c00128"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113741"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001608200"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09197"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.8b00315"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00021"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep11827"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00483.x"},{"key":"e_1_2_6_16_1","doi-asserted-by":"crossref","unstructured":"M.Gellert M. 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