title: Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients.
abstract: The opportunistic pathogen Pseudomonas aeruginosa undergoes genetic change during chronic airway infection of cystic fibrosis (CF) patients. One common change is a mutation inactivating lasR, which encodes a transcriptional regulator that responds to a homoserine lactone signal to activate expression of acute virulence factors. Colonies of lasR mutants visibly accumulated the iridescent intercellular signal 4-hydroxy-2-heptylquinoline. Using this colony phenotype, we identified P. aeruginosa lasR mutants that emerged in the airway of a CF patient early during chronic infection, and during growth in the laboratory on a rich medium. The lasR loss-of-function mutations in these strains conferred a growth advantage with particular carbon and nitrogen sources, including amino acids, in part due to increased expression of the catabolic pathway regulator CbrB. This growth phenotype could contribute to selection of lasR mutants both on rich medium and within the CF airway, supporting a key role for bacterial metabolic adaptation during chronic infection. Inactivation of lasR also resulted in increased beta-lactamase activity that increased tolerance to ceftazidime, a widely used beta-lactam antibiotic. Loss of LasR function may represent a marker of an early stage in chronic infection of the CF airway with clinical implications for antibiotic resistance and disease progression.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: D'Argenio
authors.forename: Manhong
authors.initials: M
authors.lastname: Wu
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Hoffman
authors.forename: Hemantha D
authors.initials: HD
authors.lastname: Kulasekara
authors.forename: Eric
authors.initials: E
authors.lastname: Déziel
authors.forename: Eric E
authors.initials: EE
authors.lastname: Smith
authors.forename: Hai
authors.initials: H
authors.lastname: Nguyen
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Larson Freeman
authors.forename: David H
authors.initials: DH
authors.lastname: Spencer
authors.forename: Mitchell
authors.initials: M
authors.lastname: Brittnacher
authors.forename: Hillary S
authors.initials: HS
authors.lastname: Hayden
authors.forename: Sara
authors.initials: S
authors.lastname: Selgrade
authors.forename: Mikkel
authors.initials: M
authors.lastname: Klausen
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burns
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects; D000483:Alleles; D000577:Amides / Q000494:pharmacology; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002442:Ceftazidime / Q000494:pharmacology; D019070:Cell Lineage / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000382:microbiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000302:isolation & purification; D011804:Quinolines / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000382:microbiology*; D019802:Succinic Acid / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000577:Amides; D000596:Amino Acids; D001426:Bacterial Proteins; C432142:CbrB protein, Pseudomonas aeruginosa; D004268:DNA-Binding Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D050505:Mutant Proteins; D011804:Quinolines; D015534:Trans-Activators; D014157:Transcription Factors; C013083:lactamide; D002442:Ceftazidime; D019802:Succinic Acid; D001618:beta-Lactamases