{"doi":"10.3390/molecules31010029","title":"Cyclic Amide-Linked Oxazolidinone Triazoles as Inhibitors of the T-Box Riboswitch","abstract":"Antimicrobial resistance remains a critical global health challenge, and was intensified by the COVID-19 pandemic. To address this growing threat, novel antibacterial agents targeting unconventional mechanisms are urgently needed. One promising strategy involves inhibiting bacterial riboswitches-RNA elements that regulate gene expression. Unlike most riboswitches that respond to small-molecule metabolites, the T-box riboswitch uniquely binds non-aminoacylated tRNA and is predominantly found in Gram-positive bacteria, making it an attractive target due to its conserved sequences and regulatory role over essential genes. This study explored oxazolidinone- and triazole-based compounds as potential inhibitors of the T-box riboswitch. Prior investigations into tricyclic oxazolidinones revealed an allosteric modulator that effectively inhibited T-box riboswitch transcriptional readthrough in vitro, though it showed limited disruption of the isolated tRNA-antiterminator complex. To enhance RNA-binding affinity and stereoselectivity, a macrocyclic oxazolidinone scaffold was designed, incorporating a strategic substituent to expand the interaction footprint. A synthetically viable candidate was identified, and computational docking studies suggested that one of the designed compounds may interfere with tRNA-induced transcription by forming π-π stacking interactions with G5 in the antiterminator region. These findings support the potential of targeting the T-box riboswitch with structurally optimized small molecules as a novel antibacterial strategy.","journal":"Molecules","year":2025,"id":586580,"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":0.9539,"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":447809,"name":"Ali H. Aldhumani","orcid":"0000-0002-1898-8147","position":1,"is_corresponding":false},{"id":715357,"name":"Emily A. Fairchild","orcid":"0000-0002-0226-6801","position":2,"is_corresponding":false},{"id":1501570,"name":"Oluwaseun B. Adegbite","orcid":null,"position":3,"is_corresponding":false},{"id":1501169,"name":"Jessica M. Roberts","orcid":"0000-0003-3164-7256","position":4,"is_corresponding":false},{"id":447812,"name":"Jennifer V. Hines","orcid":"0000-0001-9812-3137","position":5,"is_corresponding":false},{"id":447811,"name":"Stephen C. Bergmeier","orcid":"0000-0003-3891-8442","position":6,"is_corresponding":false},{"id":448580,"name":"Eric Parsons","orcid":null,"position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T02:59:32.191237Z","pmid":"41515326","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":[]}