{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:31:24Z","timestamp":1768213884642,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["FSFZ-2026-0007"],"award-info":[{"award-number":["FSFZ-2026-0007"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This work describes the lead optimization of a promising class of antibacterial compounds, derived from a previously reported N-[4-(4-fluorophenoxy)phenyl]-6-(methylsulfonyl)-2,6-diazaspiro [3.4]octane-8-carboxamide (LK1819), through systematic scaffold simplification. A novel series of amide derivatives were designed and synthesized, exploring key structural variations, including the replacement of the diphenyl ether core with a biphenyl system. All compounds were evaluated for in vitro antibacterial activity against the ESKAPE panel of pathogens. The most potent simplified analogs demonstrated exceptional, broad-spectrum activity, with minimum inhibitory concentrations (MICs) that were 10 to 100 times lower than the control antibiotic ciprofloxacin against many strains. Mechanistic studies using a reporter system and enzymatic assays revealed that the compounds do not inhibit protein synthesis but disrupt DNA replication, exhibiting a dose-dependent inhibitory effect on bacterial topoisomerase I and DNA gyrase. The compounds showed moderate toxicity against human cell lines, consistent with their DNA-targeting mechanism, but cytotoxicity assays indicated a sufficient selectivity window. We conclude that scaffold simplification successfully yielded highly potent antibacterial agents with a defined mechanism of action, presenting a promising foundation for further development as antibiotics and potentially as anticancer agents.<\/jats:p>","DOI":"10.3390\/molecules31020240","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T07:30:34Z","timestamp":1768203034000},"page":"240","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Scaffold Simplification Yields Potent Antibacterial Agents That Target Bacterial Topoisomerases"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5410-9333","authenticated-orcid":false,"given":"Lyubov","family":"Khudiakova","sequence":"first","affiliation":[{"name":"Lomonosov Institute of Fine Chemical Technologies, MIREA\u2014Russian Technological University, Moscow 119454, 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Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9115-3250","authenticated-orcid":false,"given":"Lyudmila","family":"Kraeva","sequence":"additional","affiliation":[{"name":"Pasteur Institute of Epidemiology and Microbiology, Saint Petersburg 197101, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-1210","authenticated-orcid":false,"given":"Olga","family":"Shevtsova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, GSP-1, 1-3 Leninskiye Gory, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daria","family":"Ipatova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, GSP-1, 1-3 Leninskiye Gory, Moscow 119991, 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