{"doi":"10.1073/pnas.2025172118","title":"Potency boost of a <i>Mycobacterium tuberculosis</i> dihydrofolate reductase inhibitor by multienzyme F <sub>420</sub> H <sub>2</sub> -dependent reduction","abstract":"Significance Bacterial metabolism can cause intrinsic drug resistance but can also convert inactive parent drugs into bioactive derivatives, as is the case for several antimycobacterial prodrugs. Here, we show that the intrabacterial metabolism of a Mtb dihydrofolate reductase (DHFR) inhibitor with moderate affinity for its target boosts its on-target activity by two orders of magnitude. This is a “prodrug-like” antimycobacterial that possesses baseline activity in the absence of intracellular bioactivation. By elucidating the metabolic enhancement mechanism, we have provided the basis for the rational optimization of a class of DHFR inhibitors and uncovered an antibacterial drug discovery concept.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":187864,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294168,"name":"Brendon M. Lee","orcid":"0000-0001-6476-5246","position":1,"is_corresponding":false},{"id":748037,"name":"Xuan Yang","orcid":"0000-0002-3480-9065","position":2,"is_corresponding":false},{"id":294414,"name":"Matthew Zimmerman","orcid":"0000-0002-6229-0571","position":3,"is_corresponding":false},{"id":270338,"name":"Martin Gengenbacher","orcid":"0000-0002-0208-5920","position":4,"is_corresponding":false},{"id":283116,"name":"Véronique Dartois","orcid":"0000-0001-9470-5009","position":5,"is_corresponding":false},{"id":748038,"name":"Wai‐Keung Chui","orcid":"0000-0003-2568-6021","position":6,"is_corresponding":false},{"id":294181,"name":"Colin J. Jackson","orcid":"0000-0001-6150-3822","position":7,"is_corresponding":false},{"id":270341,"name":"Thomas Dick","orcid":"0000-0002-9604-9452","position":8,"is_corresponding":false},{"id":699727,"name":"Wassihun Wedajo Aragaw","orcid":"0000-0002-4199-2224","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:49:05.976005Z","pmid":"34161270","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":[]}