title: Sputum containing zinc enhances carbapenem resistance, biofilm formation and virulence of Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa chronic lung infections are the leading cause of mortality in cystic fibrosis patients, a serious problem which is notably due to the numerous P. aeruginosa virulence factors, to its ability to form biofilms and to resist the effects of most antibiotics. Production of virulence factors and biofilm formation by P. aeruginosa is highly coordinated through complex regulatory systems. We recently found that CzcRS, the zinc and cadmium-specific two-component system is not only involved in metal resistance, but also in virulence and carbapenem antibiotic resistance in P. aeruginosa. Interestingly, zinc has been shown to be enriched in the lung secretions of cystic fibrosis patients. In this study, we investigated whether zinc might favor P. aeruginosa pathogenicity using an artificial sputum medium to mimic the cystic fibrosis lung environment. Our results show that zinc supplementation triggers a dual P. aeruginosa response: (i) it exacerbates pathogenicity by a CzcRS two-component system-dependent mechanism and (ii) it stimulates biofilm formation by a CzcRS-independent mechanism. Furthermore, P. aeruginosa cells embedded in these biofilms exhibited increased resistance to carbapenems. We identified a novel Zn-sensitive regulatory circuit controlling the expression of the OprD porin and modifying the carbapenem resistance profile. Altogether our data demonstrated that zinc levels in the sputum of cystic fibrosis patients might aggravate P. aeruginosa infection. Targeting zinc levels in sputum would be a valuable strategy to curb the increasing burden of P. aeruginosa infections in cystic fibrosis patients.
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, Sciences III, University of Geneva, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Marguerettaz
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, Sciences III, University of Geneva, Switzerland.
authors.forename: Guennaëlle
authors.initials: G
authors.lastname: Dieppois
authors.affiliation: Service of Adult Intensive Care Medicine & Burns, Lausanne University Hospital, CHUV BH-08,612, Switzerland.
authors.forename: Yok Ai
authors.initials: YA
authors.lastname: Que
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, Sciences III, University of Geneva, Switzerland.
authors.forename: Véréna
authors.initials: V
authors.lastname: Ducret
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, Sciences III, University of Geneva, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Zuchuat
authors.affiliation: Microbiology Unit, Department of Botany and Plant Biology, Sciences III, University of Geneva, Switzerland. Electronic address: karl.perron@unige.ch.
authors.forename: Karl
authors.initials: K
authors.lastname: Perron
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000254:growth & development*; D015780:Carbapenems / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000502:physiology; D015398:Signal Transduction; D013183:Sputum / Q000737:chemistry* / Q000382:microbiology*; D014774:Virulence; D015032:Zinc / Q000032:analysis* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D026901:Membrane Transport Proteins; D015032:Zinc
keywords: Biofilm; Carbapenem; Cystic fibrosis; Pseudomonas aeruginosa; Sputum; Virulence; Zinc