{"doi":"10.3390/pathogens11101102","title":"Serendipitous Discovery of a Competitive Inhibitor of FraB, a Salmonella Deglycase and Drug Target","abstract":"Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no Salmonella-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a Salmonella deglycase responsible for fructose-asparagine catabolism, is a viable drug target, we initiated experimental and computational efforts to identify inhibitors of FraB. To this end, our recent high-throughput screening initiative yielded almost exclusively uncompetitive inhibitors of FraB. In parallel with this advance, we report here how a separate structural and computational biology investigation of FrlB, a FraB paralog, led to the serendipitous discovery that 2-deoxy-6-phosphogluconate is a competitive inhibitor of FraB (KI ~ 3 μM). However, this compound was ineffective in inhibiting the growth of Salmonella in a liquid culture. In addition to poor uptake, cellular metabolic transformations by a Salmonella dehydrogenase and different phosphatases likely undermined the efficacy of 2-deoxy-6-phosphogluconate in live-cell assays. These insights inform our ongoing efforts to synthesize non-hydrolyzable/-metabolizable analogs of 2-deoxy-6-phosphogluconate. We showcase our findings largely to (re)emphasize the role of serendipity and the importance of multi-pronged approaches in drug discovery.","journal":"Pathogens","year":2022,"id":290453,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":828145,"name":"Sravya Kovvali","orcid":null,"position":1,"is_corresponding":false},{"id":973370,"name":"Austin M. Cool","orcid":null,"position":2,"is_corresponding":false},{"id":307995,"name":"Yuan Gao","orcid":"0000-0002-1762-0121","position":3,"is_corresponding":false},{"id":936796,"name":"Anice Sabag-Daigle","orcid":"0000-0002-5323-1588","position":4,"is_corresponding":false},{"id":972866,"name":"Erin F. Boulanger","orcid":"0000-0003-3550-528X","position":5,"is_corresponding":false},{"id":924959,"name":"Mark J. Mitton‐Fry","orcid":"0000-0002-6715-8836","position":6,"is_corresponding":false},{"id":411891,"name":"Angela Di Capua","orcid":"0000-0001-6960-0715","position":7,"is_corresponding":false},{"id":328501,"name":"Edward J. Behrman","orcid":"0000-0002-8797-6625","position":8,"is_corresponding":false},{"id":242368,"name":"Vicki H. Wysocki","orcid":"0000-0003-0495-2538","position":9,"is_corresponding":false},{"id":308314,"name":"Steffen Lindert","orcid":"0000-0002-3976-3473","position":10,"is_corresponding":false},{"id":603259,"name":"Brian M. M. Ahmer","orcid":"0000-0002-4267-7322","position":11,"is_corresponding":false},{"id":341430,"name":"Venkat Gopalan","orcid":"0000-0002-3016-2719","position":12,"is_corresponding":false},{"id":764117,"name":"Pankajavalli Thirugnanasambantham","orcid":null,"position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T00:30:30.639224Z","pmid":"36297159","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":[]}