title: The Pseudomonas aeruginosa CreBC two-component system plays a major role in the response to β-lactams, fitness, biofilm growth, and global regulation.
abstract: Pseudomonas aeruginosa is a ubiquitous versatile environmental microorganism with a remarkable ability to grow under diverse environmental conditions. Moreover, P. aeruginosa is responsible for life-threatening infections in immunocompromised and cystic fibrosis patients, as the extraordinary capacity of this pathogen to develop antimicrobial resistance dramatically limits our therapeutic arsenal. Its large genome carries an outstanding number of genes belonging to regulatory systems, including multiple two-component sensor-regulator systems that modulate the response to the different environmental stimuli. Here, we show that one of two systems, designated CreBC (carbon source responsive) and BlrAB (β-lactam resistance), might be of particular relevance. We first identified the stimuli triggering the activation of the CreBC system, which specifically responds to penicillin-binding protein 4 (PBP4) inhibition by certain β-lactam antibiotics. Second, through an analysis of a large comprehensive collection of mutants, we demonstrate an intricate interconnection between the CreBC system, the peptidoglycan recycling pathway, and the expression of the concerning chromosomal β-lactamase AmpC. Third, we show that the CreBC system, and particularly its effector inner membrane protein CreD, plays a major role in bacterial fitness and biofilm development, especially in the presence of subinhibitory concentrations of β-lactams. Finally, global transcriptomics reveals broad regulatory functions of CreBC in basic physiological aspects, particularly anaerobic respiration, in both the presence and absence of antibiotics. Therefore, the CreBC system is envisaged as a potentially interesting target for improving the efficacy of β-lactams against P. aeruginosa infections.
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Zamorano
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain bartolome.moya@ssib.es antonio.oliver@ssib.es.
authors.forename: Bartolomé
authors.initials: B
authors.lastname: Moyà
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Juan
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mulet
authors.affiliation: Instituto de Biomedicina de Sevilla, Seville, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Blázquez
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain bartolome.moya@ssib.es antonio.oliver@ssib.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
mesh_terms: D001426:Bacterial Proteins / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development*; D008565:Membrane Proteins / Q000235:genetics; D046915:Penicillin-Binding Proteins / Q000235:genetics; D010457:Peptidoglycan / Q000235:genetics; D011552:Pseudomonas Infections / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics*; D018440:beta-Lactam Resistance / Q000235:genetics; D001618:beta-Lactamases / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; C048795:AmpC beta-lactamases; D001618:beta-Lactamases