{"doi":"10.1016/j.celrep.2020.108313","title":"CrrB Positively Regulates High-Level Polymyxin Resistance and Virulence in Klebsiella pneumoniae","abstract":"Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through chemical modification of the lipid A portion of lipopolysaccharide. Various mutations are implicated in PR, including in three two-component systems-CrrA/B, PmrA/B, and PhoP/Q-and the negative regulator MgrB. Few have been functionally validated. Therefore, here we adapt a CRISPR-Cas9 system to CRKP to elucidate how mutations in clinical CRKP isolates induce PR. We demonstrate that CrrB is a positive regulator of PR, and common clinical mutations lead to the addition of both 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosophethanolamine (pEtN) to lipid A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption. Additionally, crrB mutations cause a significant virulence increase at a fitness cost, partially from activation of the pentose phosphate pathway. Our data demonstrate the importance of CrrB in high-level PR and establish important differences across crrB alleles in balancing resistance with fitness and virulence.","journal":"Cell Reports","year":2020,"id":61251,"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":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":281545,"name":"Medini K. Annavajhala","orcid":"0000-0002-9229-8849","position":1,"is_corresponding":false},{"id":271776,"name":"Marla J. Giddins","orcid":"0000-0002-4416-4395","position":2,"is_corresponding":false},{"id":307672,"name":"Nenad Maćešić","orcid":"0000-0002-7905-628X","position":3,"is_corresponding":false},{"id":323541,"name":"Carmen M. Herrera","orcid":"0000-0002-8343-4837","position":4,"is_corresponding":false},{"id":281549,"name":"Felix D. Rozenberg","orcid":"0000-0002-5532-9773","position":5,"is_corresponding":false},{"id":323542,"name":"Gitanjali Bhushan","orcid":"0000-0002-6463-9394","position":6,"is_corresponding":false},{"id":239747,"name":"Danielle Ahn","orcid":"0000-0002-4683-4452","position":7,"is_corresponding":false},{"id":281081,"name":"Filippo Mancia","orcid":"0000-0003-3293-2200","position":8,"is_corresponding":false},{"id":323543,"name":"M. Stephen Trent","orcid":"0000-0001-6134-1800","position":9,"is_corresponding":false},{"id":246804,"name":"Anne‐Catrin Uhlemann","orcid":"0000-0002-9798-4768","position":10,"is_corresponding":false},{"id":281546,"name":"Thomas H. McConville","orcid":"0000-0002-7148-2436","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T21:09:27.985420Z","pmid":"33113377","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":[]}