title: Auto Poisoning of the Respiratory Chain by a Quorum-Sensing-Regulated Molecule Favors Biofilm Formation and Antibiotic Tolerance.
abstract: Bacterial programmed cell death and quorum sensing are direct examples of prokaryote group behaviors, wherein cells coordinate their actions to function cooperatively like one organism for the benefit of the whole culture. We demonstrate here that 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO), a Pseudomonas aeruginosa quorum-sensing-regulated low-molecular-weight excreted molecule, triggers autolysis by self-perturbing the electron transfer reactions of the cytochrome bc1 complex. HQNO induces specific self-poisoning by disrupting the flow of electrons through the respiratory chain at the cytochrome bc1 complex, causing a leak of reducing equivalents to O2 whereby electrons that would normally be passed to cytochrome c are donated directly to O2. The subsequent mass production of reactive oxygen species (ROS) reduces membrane potential and disrupts membrane integrity, causing bacterial cell autolysis and DNA release. DNA subsequently promotes biofilm formation and increases antibiotic tolerance to beta-lactams, suggesting that HQNO-dependent cell autolysis is advantageous to the bacterial populations. These data identify both a new programmed cell death system and a novel role for HQNO as a critical inducer of biofilm formation and antibiotic tolerance. This newly identified pathway suggests intriguing mechanistic similarities with the initial mitochondrial-mediated steps of eukaryotic apoptosis.
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA; Shriners Hospitals for Children Boston, Boston, MA 02114, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Hazan
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA; Shriners Hospitals for Children Boston, Boston, MA 02114, USA.
authors.forename: Yok Ai
authors.initials: YA
authors.lastname: Que
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA; Shriners Hospitals for Children Boston, Boston, MA 02114, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Maura
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Strobel
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Lausanne 1015, Switzerland.
authors.forename: Paul Anthony
authors.initials: PA
authors.lastname: Majcherczyk
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Laura Rose
authors.initials: LR
authors.lastname: Hopper
authors.affiliation: Department of Chemistry, Tufts University, Medford, MA 02155, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Wilbur
authors.affiliation: Department of Biological Sciences, CBIS, Rensselaer Polytechnic Institute, 110 8(th) Street, Troy, NY 12180, USA.
authors.forename: Teri N
authors.initials: TN
authors.lastname: Hreha
authors.affiliation: Department of Biological Sciences, CBIS, Rensselaer Polytechnic Institute, 110 8(th) Street, Troy, NY 12180, USA.
authors.forename: Blanca
authors.initials: B
authors.lastname: Barquera
authors.affiliation: Department of Surgery and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Center for Surgery, Innovation and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA; Shriners Hospitals for Children Boston, Boston, MA 02114, USA. Electronic address: rahme@molbio.mgh.harvard.edu.
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms; D004579:Electron Transport / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006912:Hydroxyquinolines / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D053038:Quorum Sensing / Q000187:drug effects / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006912:Hydroxyquinolines; C001333:2-(n-heptyl)-4-hydroxyquinoline N-oxide