{"doi":"10.1002/ange.202300221","title":"Chemical Validation of <i>Mycobacterium tuberculosis</i> Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference**","abstract":"Abstract The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much‐needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis ( Mtb ). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase ( Mtb PPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the Mtb PPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X‐ray crystal structures, we could link weakly‐binding fragments to produce an active site binder with a K D &lt;20 μM and on‐target anti‐ Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating Mtb PPAT as a potential drug target and designing a Mtb PPAT‐targeting anti‐TB drug.","journal":"Angewandte Chemie","year":2023,"id":387830,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"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":770490,"name":"M. Blasz̧czyk","orcid":"0000-0001-5728-1518","position":1,"is_corresponding":false},{"id":696432,"name":"Joanna C. Evans","orcid":"0000-0002-4139-9527","position":2,"is_corresponding":false},{"id":1107867,"name":"Jennifer A. Boland","orcid":null,"position":3,"is_corresponding":false},{"id":955222,"name":"William J. McCarthy","orcid":"0000-0002-2858-076X","position":4,"is_corresponding":false},{"id":1107394,"name":"Imam Fathoni","orcid":"0000-0003-3343-8917","position":5,"is_corresponding":false},{"id":1107395,"name":"M.V.B. Dias","orcid":"0000-0002-5312-0191","position":6,"is_corresponding":false},{"id":1107396,"name":"Eachan O. Johnson","orcid":"0000-0002-0335-8337","position":7,"is_corresponding":false},{"id":331046,"name":"Anthony G. Coyne","orcid":"0000-0003-0205-5630","position":8,"is_corresponding":false},{"id":655318,"name":"Valerie Mizrahi","orcid":"0000-0003-4824-9115","position":9,"is_corresponding":false},{"id":329601,"name":"Tom L. Blundell","orcid":"0000-0002-2708-8992","position":10,"is_corresponding":false},{"id":331047,"name":"Chris Abell","orcid":"0000-0001-9174-1987","position":11,"is_corresponding":false},{"id":770491,"name":"Christina Spry","orcid":"0000-0002-8156-7070","position":12,"is_corresponding":false},{"id":955223,"name":"Jamal El Bakali","orcid":"0000-0002-1470-0521","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:18:08.845494Z","pmid":"38515507","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":[]}