{"doi":"10.1101/2022.06.27.497815","title":"Structure-Uptake Relationship Studies of Oxazolidinones in Gram-negative ESKAPE Pathogens","abstract":"Abstract To date, little is known about applicability and/or generality of molecular features and how they impact small molecule permeation into Gram-negative bacteria. Identifying motifs or structural trends that correlate with broad and/or species-specific permeation would enable the rational design of new antibacterials. The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. E. coli, A. baumannii , and P. aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer-membrane and/or enhance efflux susceptibility broadly and specifically between species. The results of this study illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogs ( 3e , 12f , and 14 ) were identified from this study that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":309522,"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":0.9526,"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":511442,"name":"Inga V. Leus","orcid":"0000-0001-8906-717X","position":1,"is_corresponding":false},{"id":1004488,"name":"Brinda Chandar","orcid":"0000-0002-6766-7542","position":2,"is_corresponding":false},{"id":1004489,"name":"Bradley Sherborne","orcid":"0000-0002-0037-3427","position":3,"is_corresponding":false},{"id":1004816,"name":"Quentin P. Avila","orcid":null,"position":4,"is_corresponding":false},{"id":581359,"name":"Valentin V. Rybenkov","orcid":"0000-0002-5300-4369","position":5,"is_corresponding":false},{"id":274353,"name":"Helen I. Zgurskaya","orcid":"0000-0001-8929-4727","position":6,"is_corresponding":false},{"id":385971,"name":"Adam S. Duerfeldt","orcid":"0000-0002-3130-9890","position":7,"is_corresponding":false},{"id":138515,"name":"Ziwei Hu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:33:11.579763Z","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":[]}