{"doi":"10.1128/jb.00189-25","title":"The PA2803-encoded PcrP exhibits a novel non-catalytic function and contributes to polymyxin B resistance in <i>P. aeruginosa</i>","abstract":"ABSTRACT The opportunistic human pathogen Pseudomonas aeruginosa ( Pa ), a leading cause of severe infections, becomes increasingly resistant to antibiotics, including the last resort antibiotic, polymyxin B (PMB). Previous studies have shown that calcium (Ca 2+ ) at the levels encountered during infections increases Pa resistance to PMB. However, the mechanisms of this Ca 2+ regulation are not known. Here, we identified three novel genes ( PA2803, PA3237 , and PA5317 ) that contribute to the Ca 2+ -dependent PMB resistance in Pa. PA2803 , the focus of this work, encodes a putative phosphonatase and is a founding member of the PA2803 subfamily from the Haloacid Dehalogenase Superfamily. Since the transcription of this gene is regulated by both Ca 2+ and inorganic phosphate (P i ), we named it “P i and Ca 2+ -regulated protein, PcrP.” Congruent with sequence-based predictions, we showed that PcrP lacks catalytic activity and instead binds protein partners, revealing a novel non-catalytic function. By using pull-down assays and bacterial two-hybrid systems, we identified and validated two protein partners of PcrP: Acp3 and PA3518. We showed that PcrP is involved in oxidative stress responses in Pa , which are likely mediated by its interactions with Acp3 and may support its role in PMB resistance. In addition, PcrP imparts a Ca 2+ -dependent growth advantage during P i starvation and plays a role in polyphosphate accumulation in a Ca 2+ -dependent manner. Overall, this study identified a novel protein-binding function for the PA2803 subfamily representative, which mediates Pa responses to elevated Ca 2+ and P i starvation and enhances PMB resistance. IMPORTANCE Pseudomonas aeruginosa ( Pa ) is a critical human pathogen that presents significant clinical challenges, underscoring the urgent need for understanding its resistance mechanisms. Previous studies have shown that calcium (Ca 2+ ) at the levels detected during infections increases Pa resistance to the last resort antibiotic polymyxin B (PMB). For the first time, we identified three novel genes, whose products are required for the Ca 2+ -dependent PMB resistance in Pa . One of them, PA2803 , regulated by Ca 2+ and phosphate, was named phosphate and Ca 2+ -regulated protein, PcrP. This study discovered a novel protein-binding function of PcrP and identified two protein partners. Given the high level of sequence conservation within the PA2803 subfamily, the protein-binding function may be shared by other members of the PA2803 subfamily.","journal":"Journal of Bacteriology","year":2025,"id":547768,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":true,"deposit_databanks":{"SRA":["PRJNA703087"]},"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":1440558,"name":"Sabina Khanam","orcid":"0000-0002-0956-5783","position":1,"is_corresponding":false},{"id":325934,"name":"Veniamin A. Borin","orcid":"0000-0001-7832-1443","position":2,"is_corresponding":false},{"id":1440990,"name":"M. Achour","orcid":null,"position":3,"is_corresponding":false},{"id":1440991,"name":"Deok‐Kun Oh","orcid":null,"position":4,"is_corresponding":false},{"id":1440992,"name":"Mert Kanik","orcid":null,"position":5,"is_corresponding":false},{"id":1440993,"name":"Prasadi Gallage","orcid":null,"position":6,"is_corresponding":false},{"id":9211,"name":"A. Khanov","orcid":"0000-0001-9621-422X","position":7,"is_corresponding":false},{"id":1440994,"name":"Mendi Hull","orcid":null,"position":8,"is_corresponding":false},{"id":1299022,"name":"Spencer P. Pitre","orcid":"0000-0001-6161-7133","position":9,"is_corresponding":false},{"id":1440559,"name":"P. K. Agarwal","orcid":"0000-0002-6727-2137","position":10,"is_corresponding":false},{"id":745183,"name":"Michael J. Franklin","orcid":"0000-0002-4587-6546","position":11,"is_corresponding":false},{"id":919578,"name":"Marianna A. Patrauchan","orcid":"0000-0002-0495-3867","position":12,"is_corresponding":false},{"id":1440557,"name":"Tarosha Salpadoru","orcid":"0000-0002-3711-5501","position":0,"is_corresponding":true}],"reference_count":160,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41104944","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":[]}