{"doi":"10.1128/aac.00474-23","title":"Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and <i>in vivo</i> efficacy","abstract":"ABSTRACT Nitro-containing compounds have emerged as important agents in the control of tuberculosis (TB). From a whole-cell high-throughput screen for Mycobacterium tuberculosis (Mtb) growth inhibitors, 10 nitro-containing compounds were prioritized for characterization and mechanism of action studies. HC2209, HC2210, and HC2211 are nitrofuran-based prodrugs that need the cofactor F 420 machinery for activation. Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F 420 -dependent reductase for activation. These nitrofurans also differ from pretomanid in their potent activity against Mycobacterium abscessus . Four dinitrobenzamides (HC2217, HC2226, HC2238, and HC2239) and a nitrofuran (HC2250) are proposed to be inhibitors of decaprenyl-phosphoryl-ribose 2′-epimerase 1 (DprE1), based on isolation of resistant mutations in dprE1 . Unlike other DprE1 inhibitors, HC2250 was found to be potent against non-replicating persistent bacteria, suggesting additional targets. Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb in vitro , but a proposed mechanism of action could not be defined. In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.","journal":"Antimicrobial Agents and Chemotherapy","year":2023,"id":348307,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":312549,"name":"John T. Williams","orcid":"0000-0002-2742-1636","position":1,"is_corresponding":false},{"id":1090996,"name":"Elizabeth R. Haiderer","orcid":null,"position":2,"is_corresponding":false},{"id":1090997,"name":"Verónica Albrecht","orcid":null,"position":3,"is_corresponding":false},{"id":1090998,"name":"Heather M. Murdoch","orcid":null,"position":4,"is_corresponding":false},{"id":1090999,"name":"Bassel J. Abdalla","orcid":null,"position":5,"is_corresponding":false},{"id":312550,"name":"Robert B. Abramovitch","orcid":"0000-0002-4119-4169","position":6,"is_corresponding":false},{"id":422089,"name":"Ifeanyichukwu E. Eke","orcid":"0000-0001-9790-7589","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:12:06.040073Z","pmid":"37610224","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":[]}