{"doi":"10.1128/aac.00717-23","title":"Pharmacological validation of dihydrofolate reductase as a drug target in <i>Mycobacterium abscessus</i>","abstract":"ABSTRACT The Mycobacterium abscessus drug development pipeline is poorly populated, with particularly few validated target-lead couples to initiate de novo drug discovery. Trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) used for the treatment of a range of bacterial infections, is not active against M. abscessus . Thus, evidence that M. abscessus DHFR is vulnerable to pharmacological intervention with a small molecule inhibitor is lacking. Here, we show that the pyrrolo-quinazoline PQD-1, previously identified as a DHFR inhibitor active against Mycobacterium tuberculosis , exerts whole cell activity against M. abscessus . Enzyme inhibition studies showed that PQD-1, in contrast to trimethoprim, is a potent inhibitor of M. abscessus DHFR and over-expression of DHFR causes resistance to PQD-1, providing biochemical and genetic evidence that DHFR is a vulnerable target and mediates PQD-1’s growth inhibitory activity in M. abscessus . As observed in M. tuberculosis , PQD-1 resistant mutations mapped to the folate pathway enzyme thymidylate synthase (TYMS) ThyA. Like trimethoprim in other bacteria, PQD-1 synergizes with the dihydropteroate synthase (DHPS) inhibitor sulfamethoxazole (SMX), offering an opportunity to exploit the successful dual inhibition of the folate pathway and develop similarly potent combinations against M. abscessus . PQD-1 is active against subspecies of M. abscessus and a panel of clinical isolates, providing epidemiological validation of the target-lead couple. Leveraging a series of PQD-1 analogs, we have demonstrated a dynamic structure-activity relationship (SAR). Collectively, the results identify M. abscessus DHFR as an attractive target and PQD-1 as a chemical starting point for the discovery of novel drugs and drug combinations that target the folate pathway in M. abscessus .","journal":"Antimicrobial Agents and Chemotherapy","year":2023,"id":341928,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"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":283115,"name":"Dereje A. Negatu","orcid":"0000-0001-9205-6842","position":1,"is_corresponding":false},{"id":954948,"name":"Christopher J. Bungard","orcid":"0000-0002-2523-5266","position":2,"is_corresponding":false},{"id":283116,"name":"Véronique Dartois","orcid":"0000-0001-9470-5009","position":3,"is_corresponding":false},{"id":954946,"name":"Abdellatif El Marrouni","orcid":"0000-0001-5408-0374","position":4,"is_corresponding":false},{"id":1077973,"name":"Elliott Nickbarg","orcid":"0000-0003-2929-4455","position":5,"is_corresponding":false},{"id":655319,"name":"David B. Olsen","orcid":"0000-0001-5521-0206","position":6,"is_corresponding":false},{"id":1005485,"name":"Ralf Warrassꝉ","orcid":null,"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":45,"raw_metadata":null,"created_at":"2026-07-19T01:11:08.077724Z","pmid":"38018963","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":[]}