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Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug\u2010resistant Gram\u2010negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese\u2010containing UDP\u20102,3\u2010diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram\u2010negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with <jats:italic>K. pneumoniae<\/jats:italic> LpxH (<jats:italic>Kp<\/jats:italic>LpxH), here we report the development and structural validation of the first\u2010in\u2010class sulfonyl piperazine LpxH inhibitors, JH\u2010LPH\u201045 (<jats:bold>8<\/jats:bold>) and JH\u2010LPH\u201050 (<jats:bold>13<\/jats:bold>), that achieve chelation of the active site dimanganese cluster of <jats:italic>Kp<\/jats:italic>LpxH. The chelation of the dimanganese cluster significantly improves the potency of JH\u2010LPH\u201045 (<jats:bold>8<\/jats:bold>) and JH\u2010LPH\u201050 (<jats:bold>13<\/jats:bold>). We expect that further optimization of these proof\u2010of\u2010concept dimanganese\u2010chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug\u2010resistant Gram\u2010negative pathogens.<\/jats:p>","DOI":"10.1002\/cmdc.202300023","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T11:36:20Z","timestamp":1680608180000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-3412","authenticated-orcid":false,"given":"Seung\u2010Hwa","family":"Kwak","sequence":"first","affiliation":[{"name":"Department of Chemistry Duke University  Durham NC 27708 USA"},{"name":"Current address: Ambagon Therapeutics Inc.  953 Indiana Street San Francisco CA 94107 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