{"doi":"10.1128/aac.00078-25","title":"Structure and mechanism of taniborbactam inhibition of the cefepime-hydrolyzing, partial R2-loop deletion <i>Pseudomonas</i> -derived cephalosporinase variant PDC-88","abstract":"ABSTRACT Pseudomonas aeruginosa is a major gram-negative pathogen responsible for a variety of infections and possessing an array of both intrinsic and acquired resistance mechanisms, including β-lactamases, like the chromosomal Pseudomonas -derived cephalosporinase (PDC). β-Lactams are the most widely prescribed class of antibiotics in the United States, and antipseudomonal cephalosporins (including cefepime) are important therapies (alone or combined with β-lactamase inhibitors) for P. aeruginosa infections. Taniborbactam is a novel, bicyclic boronate β-lactamase inhibitor with activity against all β-lactamase classes and is being developed in combination with cefepime. PDC-88 is an R2-loop deletion variant conferring resistance to cefepime and ceftazidime and elevating ceftolozane/tazobactam minimum inhibitory concentration (MIC). Herein, we elucidated PDC-88 resistance mechanisms and compared inhibition by taniborbactam and avibactam. In an isogenic background, PDC-88 increased cefepime MICs by 16-fold compared to PDC-3. In vitro , compared to PDC-3, PDC-88 had 8.3-fold higher catalytic efficiency for cefepime achieved by decreasing K M 12.8-fold and decreasing k cat 1.6-fold. This is supported by our crystallographic observation that the PDC-88 deletion enlarged the active site in the vicinity of the R2-loop, likely better accommodating cefepime. Taniborbactam and avibactam restored cefepime activity by inhibiting PDC-88. Compared to avibactam, taniborbactam had 4.1- and 9-fold lower K i app values for PDC-3 and PDC-88, respectively, with higher k on ( k 2 / K ) and similar k off for both enzymes. Structurally, taniborbactam positioned very similarly in the PDC-3 and PDC-88 active sites, interacting with many nearby residues. Based upon these data, cefepime-taniborbactam may represent an important alternative to ceftazidime-avibactam and ceftolozane-tazobactam for P. aeruginosa infections.","journal":"Antimicrobial Agents and Chemotherapy","year":2025,"id":541468,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"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":383556,"name":"Vijay Kumar","orcid":"0000-0002-2741-8891","position":1,"is_corresponding":false},{"id":384425,"name":"Christopher R. Bethel","orcid":null,"position":2,"is_corresponding":false},{"id":272734,"name":"Magdalena A. Taracila","orcid":null,"position":3,"is_corresponding":false},{"id":859777,"name":"Brittany Miller","orcid":null,"position":4,"is_corresponding":false},{"id":1218567,"name":"Tsuyoshi Uehara","orcid":"0000-0001-6994-4286","position":5,"is_corresponding":false},{"id":887202,"name":"David A. Six","orcid":"0000-0002-9013-1711","position":6,"is_corresponding":false},{"id":270505,"name":"Krisztina M. Papp‐Wallace","orcid":"0000-0002-9976-7898","position":7,"is_corresponding":false},{"id":383557,"name":"Focco van den Akker","orcid":"0000-0001-9210-3565","position":8,"is_corresponding":false},{"id":232761,"name":"Robert A. Bonomo","orcid":"0000-0002-3299-894X","position":9,"is_corresponding":false},{"id":270506,"name":"Andrew R Mack","orcid":"0000-0002-0131-7996","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:52:47.161928Z","pmid":"40503958","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":[]}