{"doi":"10.1002/anie.202211498","title":"Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance","abstract":"Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.","journal":"Angewandte Chemie International Edition","year":2022,"id":252932,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":319076,"name":"Uday S. Ganapathy","orcid":null,"position":1,"is_corresponding":false},{"id":897656,"name":"Sachin Sharma","orcid":"0000-0002-3941-7992","position":2,"is_corresponding":false},{"id":719948,"name":"Yong‐Mo Ahn","orcid":null,"position":3,"is_corresponding":false},{"id":294414,"name":"Matthew Zimmerman","orcid":"0000-0002-6229-0571","position":4,"is_corresponding":false},{"id":554382,"name":"Vadim Molodtsov","orcid":"0000-0003-3002-4794","position":5,"is_corresponding":false},{"id":734392,"name":"Pooja Hegde","orcid":null,"position":6,"is_corresponding":false},{"id":270338,"name":"Martin Gengenbacher","orcid":"0000-0002-0208-5920","position":7,"is_corresponding":false},{"id":506449,"name":"Richard H. Ebright","orcid":"0000-0001-8915-7140","position":8,"is_corresponding":false},{"id":283116,"name":"Véronique Dartois","orcid":"0000-0001-9470-5009","position":9,"is_corresponding":false},{"id":336889,"name":"Joel S. Freundlich","orcid":"0000-0002-3411-3455","position":10,"is_corresponding":false},{"id":270341,"name":"Thomas Dick","orcid":"0000-0002-9604-9452","position":11,"is_corresponding":false},{"id":381486,"name":"Courtney C. Aldrich","orcid":"0000-0001-9261-594X","position":12,"is_corresponding":false},{"id":696431,"name":"Tian Lan","orcid":"0000-0002-4099-5386","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T00:24:50.819822Z","pmid":"36222275","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":[]}