{"doi":"10.1002/cmdc.202300023","title":"Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH","abstract":"Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug-resistant Gram-negative 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-containing UDP-2,3-diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram-negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first-in-class sulfonyl piperazine LpxH inhibitors, JH-LPH-45 (8) and JH-LPH-50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH-LPH-45 (8) and JH-LPH-50 (13). We expect that further optimization of these proof-of-concept dimanganese-chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug-resistant Gram-negative pathogens.","journal":"ChemMedChem","year":2023,"id":344175,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":494198,"name":"C. Skyler Cochrane","orcid":"0000-0003-4156-2336","position":1,"is_corresponding":false},{"id":494926,"name":"Jae Cho","orcid":null,"position":2,"is_corresponding":false},{"id":1082552,"name":"Patrick A. Dome","orcid":"0000-0002-0840-5147","position":3,"is_corresponding":false},{"id":494199,"name":"Amanda F. Ennis","orcid":"0000-0002-6924-3188","position":4,"is_corresponding":false},{"id":1083096,"name":"Jea Hyun Kim","orcid":null,"position":5,"is_corresponding":false},{"id":494202,"name":"Pei Zhou","orcid":"0000-0002-7823-3416","position":6,"is_corresponding":false},{"id":494203,"name":"Jiyong Hong","orcid":"0000-0002-5253-0949","position":7,"is_corresponding":false},{"id":494197,"name":"Seung‐Hwa Kwak","orcid":"0000-0002-1360-3412","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T01:11:30.951510Z","pmid":"37014664","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}