{"doi":"10.3390/molecules30030465","title":"Exploration of the Fusidic Acid Structure Activity Space for Antibiotic Activity","abstract":". However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic acid scaffold to enhance activity against Gram-negative pathogens have not been explored. Using an activity-guided synthetic strategy, the tolerance of the tetracyclic natural product to derivatization at the A- and C-rings and its carboxylic acid side chain was explored with the goal of enhancing its activity spectrum and pharmacological properties. All side-chain carboxylic acid esters were inactive. Oxidation of the C-ring alcohol and oxime were not tolerated either. A number of esters of the A-ring alcohol retained modest activity against Gram-positive bacteria and were informative for future activity-guided studies. For the A-ring esters, differences in antibacterial activity relative to inhibitory activity in a ribosome in vitro translation assay suggested the possibility of a pro-druglike effect for the fusidic acid pyrazine-2-carboxylate. This study furthers the understanding of the activity of the fusidic acid scaffold against Gram-positive bacteria. These results suggest promise for future modification of the A-ring alcohol of fusidic acid in the advancement of its antibiotic properties.","journal":"Molecules","year":2025,"id":560662,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":780478,"name":"Simone Cavalcante Silva","orcid":"0000-0002-0257-7546","position":1,"is_corresponding":false},{"id":677847,"name":"Kenneth Smith","orcid":"0000-0003-1085-4643","position":2,"is_corresponding":false},{"id":1170325,"name":"Krissty Sumida","orcid":null,"position":3,"is_corresponding":false},{"id":1462799,"name":"Yuhan Wang","orcid":"0009-0001-7859-8394","position":4,"is_corresponding":false},{"id":812555,"name":"Lucius Chiaraviglio","orcid":"0000-0002-2613-6614","position":5,"is_corresponding":false},{"id":1462800,"name":"Ramachandra Reddy Donthiri","orcid":"0000-0002-9048-5317","position":6,"is_corresponding":false},{"id":451873,"name":"Alhanouf Z. Aljahdali","orcid":"0000-0002-6319-9702","position":7,"is_corresponding":false},{"id":262692,"name":"James E. Kirby","orcid":"0000-0003-0392-4500","position":8,"is_corresponding":false},{"id":416559,"name":"George A. O’Doherty","orcid":"0000-0002-1699-2249","position":9,"is_corresponding":false},{"id":437933,"name":"Yoon‐Suk Kang","orcid":"0000-0001-8115-1481","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:55:46.921885Z","pmid":"39942570","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":[]}