{"doi":"10.1128/aac.00787-25","title":"<i>Burkholderia pseudomallei</i> PenI β-lactamase and variants are potently inhibited by taniborbactam","abstract":"ABSTRACT Burkholderia pseudomallei is a Gram-negative pathogen that causes melioidosis, a severe and often fatal disease. Due to its recognized potential as a bioterrorism agent, it is critical that appropriate antimicrobial agents are available for post-exposure prophylaxis and treatment of melioidosis. Cefepime–taniborbactam is a novel β-lactam–β-lactamase inhibitor combination in clinical development, with promising activity against Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. Herein, we demonstrate the inhibitory activity of taniborbactam against PenI, the class A β-lactamase produced by B. pseudomallei . Isogenic Escherichia coli strains producing PenI and its ceftazidime-resistance–conferring variants (C69Y and P167S) showed ceftazidime minimum inhibitory concentration (MIC) of 64 mg/L for the strain producing PenI and 1,024 mg/L for the strains producing the variants, whereas cefepime MIC was 128–256 mg/L for these three strains. While the addition of avibactam decreased ceftazidime MIC to 1 mg/L for PenI and 8–16 mg/L for the variants, the addition of taniborbactam decreased cefepime MIC to ≤0.5 mg/L for PenI and the variants. Similarly, an 8-fold reduction of the cefepime MIC upon addition of taniborbactam was observed in an avirulent B. pseudomallei strain. Furthermore, taniborbactam inhibited PenI and its C69Y variant with an apparent K i of 0.11 and 3.1 µM, respectively. Lastly, co-crystallography and molecular dynamics simulations showed that taniborbactam induced the formation of a disulfide bond between Cys77 and Cys123, which destabilizes the deacylation water and strengthens the taniborbactam–PenI complex. These results support the development of cefepime–taniborbactam as a promising agent for the treatment of infections by B. pseudomallei .","journal":"Antimicrobial Agents and Chemotherapy","year":2025,"id":574785,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":true,"deposit_databanks":{"GENBANK":["CP002834.1","MN307371.1"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":583080,"name":"Scott A. Becka","orcid":null,"position":1,"is_corresponding":false},{"id":1339486,"name":"Mitchell Edwards","orcid":null,"position":2,"is_corresponding":false},{"id":1338984,"name":"Cullen L. Myers","orcid":"0000-0002-5789-2260","position":3,"is_corresponding":false},{"id":1339489,"name":"Kyoko Uehara","orcid":null,"position":4,"is_corresponding":false},{"id":1218567,"name":"Tsuyoshi Uehara","orcid":"0000-0001-6994-4286","position":5,"is_corresponding":false},{"id":1482447,"name":"Tyuji Hoshino","orcid":"0000-0003-4705-4412","position":6,"is_corresponding":false},{"id":1122840,"name":"Elise T. Zeiser","orcid":null,"position":7,"is_corresponding":false},{"id":667264,"name":"Cassandra L. Chatwin","orcid":null,"position":8,"is_corresponding":false},{"id":887202,"name":"David A. Six","orcid":"0000-0002-9013-1711","position":9,"is_corresponding":false},{"id":232761,"name":"Robert A. Bonomo","orcid":"0000-0002-3299-894X","position":10,"is_corresponding":false},{"id":270505,"name":"Krisztina M. Papp‐Wallace","orcid":"0000-0002-9976-7898","position":11,"is_corresponding":false},{"id":1482448,"name":"Michiyoshi Nukaga","orcid":"0000-0002-3508-3390","position":12,"is_corresponding":false},{"id":644220,"name":"María F. Mojica","orcid":"0000-0002-1380-9824","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:57:44.572630Z","pmid":"40938351","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":[]}