{"doi":"10.1128/aac.46.6.1793-1799.2002","title":"Antibacterial Activities and Characterization of Novel Inhibitors of LpxC","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-\n            <jats:italic>O</jats:italic>\n            -(\n            <jats:italic>R</jats:italic>\n            -3-hydroxymyristoyl)-\n            <jats:italic>N</jats:italic>\n            -acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an\n            <jats:italic>Escherichia coli</jats:italic>\n            strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the α-(\n            <jats:italic>R</jats:italic>\n            )-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the\n            <jats:italic>Enterobacteriaceae</jats:italic>\n            ,\n            <jats:italic>Serratia marcescens</jats:italic>\n            ,\n            <jats:italic>Morganella morganii</jats:italic>\n            ,\n            <jats:italic>Haemophilus influenzae</jats:italic>\n            ,\n            <jats:italic>Moraxella catarrhalis</jats:italic>\n            , and\n            <jats:italic>Burkholderia cepacia</jats:italic>\n            . BB-78484 was bactericidal against\n            <jats:italic>E. coli</jats:italic>\n            , achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis.\n            <jats:italic>E. coli</jats:italic>\n            mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the\n            <jats:italic>fabZ</jats:italic>\n            or\n            <jats:italic>lpxC</jats:italic>\n            genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.\n          </jats:p>","journal":"Antimicrobial Agents and Chemotherapy","year":2002,"id":647143,"datarank":0.7969808968562682,"base_score":5.313205979041787,"endowment":5.313205979041787,"self_citation_contribution":0.7969808968562682,"citation_network_contribution":0.0,"self_endowment_contribution":0.7969808968562682,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":202,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1685855,"name":"Fanny Coignard","orcid":null,"position":1,"is_corresponding":false},{"id":949392,"name":"Ian Johnson","orcid":"0000-0002-9476-6220","position":2,"is_corresponding":false},{"id":1685857,"name":"Stephen Chandler","orcid":null,"position":3,"is_corresponding":false},{"id":1685859,"name":"Shilpa Palan","orcid":null,"position":4,"is_corresponding":false},{"id":1685861,"name":"Andrew Waller","orcid":null,"position":5,"is_corresponding":false},{"id":1685862,"name":"Jac Wijkmans","orcid":null,"position":6,"is_corresponding":false},{"id":1685863,"name":"Michael G. Hunter","orcid":null,"position":7,"is_corresponding":false},{"id":415418,"name":"John M. Clements","orcid":"0000-0002-7927-8878","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Antibacterial Activities and Characterization of Novel Inhibitors of LpxC","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-\n            <jats:italic>O</jats:italic>\n            -(\n            <jats:italic>R</jats:italic>\n            -3-hydroxymyristoyl)-\n            <jats:italic>N</jats:italic>\n            -acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an\n            <jats:italic>Escherichia coli</jats:italic>\n            strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the α-(\n            <jats:italic>R</jats:italic>\n            )-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the\n            <jats:italic>Enterobacteriaceae</jats:italic>\n            ,\n            <jats:italic>Serratia marcescens</jats:italic>\n            ,\n            <jats:italic>Morganella morganii</jats:italic>\n            ,\n            <jats:italic>Haemophilus influenzae</jats:italic>\n            ,\n            <jats:italic>Moraxella catarrhalis</jats:italic>\n            , and\n            <jats:italic>Burkholderia cepacia</jats:italic>\n            . BB-78484 was bactericidal against\n            <jats:italic>E. coli</jats:italic>\n            , achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis.\n            <jats:italic>E. coli</jats:italic>\n            mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the\n            <jats:italic>fabZ</jats:italic>\n            or\n            <jats:italic>lpxC</jats:italic>\n            genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.\n          </jats:p>","is_dataset_classified":null,"base_score":5.313205979041787,"endowment":5.313205979041787,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12019092","pmcid":"PMC127247","openalex_id":"https://openalex.org/W2114197590","authors":[],"funders":[],"total_grants":0,"fwci":3.6108,"citation_percentile":0.944,"influential_citations":0,"citation_trend":[{"year":2012,"count":9},{"year":2013,"count":11},{"year":2014,"count":9},{"year":2015,"count":7},{"year":2016,"count":9},{"year":2017,"count":5},{"year":2018,"count":12},{"year":2019,"count":14},{"year":2020,"count":12},{"year":2021,"count":8},{"year":2022,"count":12},{"year":2023,"count":9},{"year":2024,"count":5},{"year":2025,"count":6},{"year":2026,"count":5}],"oa_status":"green","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/127247","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/127247","host_type":"repository"},{"url":"https://journals.asm.org/doi/pdf/10.1128/AAC.46.6.1793-1799.2002","host_type":"publisher"},{"url":"https://doi.org/10.1128/aac.46.6.1793-1799.2002","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12019092","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.322.2568","host_type":""},{"url":"http://europepmc.org/pmc/articles/PMC127247","host_type":"repository"}],"fields_of_study":["Antibiotic Resistance in Bacteria","Antimicrobial Peptides and Activities","RNA and protein synthesis mechanisms","Amidohydrolases","Anti-Bacterial Agents","Bacteria","DNA, Recombinant","Drug Resistance, Microbial","Drug Synergism","Enzyme Inhibitors","Escherichia coli","Genotype","Hydro-Lyases","Microbial Sensitivity Tests","Mutation","Naphthalenes","Plasmids","Reverse Transcriptase Polymerase Chain Reaction","Sulfonamides","Time Factors"],"mesh_terms":["Amidohydrolases","Anti-Bacterial Agents","Bacteria","DNA, Recombinant","Drug Resistance, Microbial","Drug Synergism","Enzyme Inhibitors","Escherichia coli","Genotype","Hydro-Lyases","Microbial Sensitivity Tests","Mutation","Naphthalenes","Plasmids","Sulfonamides","Time Factors","Reverse Transcriptase Polymerase Chain Reaction"],"keywords":["Lipid A","Bacterial outer membrane","Morganella morganii","Serratia marcescens","Microbiology","Escherichia coli","Biochemistry","Biology","Bacteria","Antibacterial activity","Lipopolysaccharide","Enterobacteriaceae","Moraxella catarrhalis","Minimum inhibitory concentration","Porin","Chemistry","Antibiotics","Haemophilus influenzae","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T17:03:48.955637Z","pmid":null,"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":[]}