title: The anti-cancerous drug doxorubicin decreases the c-di-GMP content in Pseudomonas aeruginosa but promotes biofilm formation.
abstract: Current antibiotic treatments are insufficient in eradicating bacterial biofilms, which represent the primary cause of chronic bacterial infections. Thus, there is an urgent need for new strategies to eradicate biofilm infections. The second messenger c-di-GMP is a positive regulator of biofilm formation in many clinically relevant bacteria. It is hypothesized that drugs lowering the intracellular level of c-di-GMP will force biofilm bacteria into a more treatable planktonic lifestyle. To identify compounds capable of lowering c-di-GMP levels in Pseudomonas aeruginosa, we screened 5000 compounds for their potential c-di-GMP-lowering effect using a recently developed c-di-GMP biosensor strain. Our screen identified the anti-cancerous drug doxorubicin as a potent c-di-GMP inhibitor. In addition, the drug decreased the transcription of many biofilm-related genes. However, despite its effect on the c-di-GMP content in P. aeruginosa, doxorubicin was unable to inhibit biofilm formation or disperse established biofilms. On the contrary, the drug was found to promote P. aeruginosa biofilm formation, possibly through release of extracellular DNA from a subpopulation of killed bacteria. Our findings emphasize that lowering of the c-di-GMP content in bacteria might not be sufficient to mediate biofilm inhibition or dispersal.
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Julie
authors.initials: J
authors.lastname: Groizeleau
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Rybtke
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens Bo
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Berthelsen
authors.affiliation: Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
authors.affiliation: Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tim
authors.initials: T
authors.lastname: Tolker-Nielsen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D004317:Doxorubicin; D006152:Cyclic GMP