title: Second messenger signalling governs Escherichia coli biofilm induction upon ribosomal stress.
abstract: Biofilms are communities of surface-attached, matrix-embedded microbial cells that can resist antimicrobial chemotherapy and contribute to persistent infections. Using an Escherichia coli biofilm model we found that exposure of bacteria to subinhibitory concentrations of ribosome-targeting antibiotics leads to strong biofilm induction. We present evidence that this effect is elicited by the ribosome in response to translational stress. Biofilm induction involves upregulation of the polysaccharide adhesin poly-beta-1,6-N-acetyl-glucosamine (poly-GlcNAc) and two components of the poly-GlcNAc biosynthesis machinery, PgaA and PgaD. Poly-GlcNAc control depends on the bacterial signalling molecules guanosine-bis 3', 5'(diphosphate) (ppGpp) and bis-(3'-5')-cyclic di-GMP (c-di-GMP). Treatment with translation inhibitors causes a ppGpp hydrolase (SpoT)-mediated reduction of ppGpp levels, resulting in specific derepression of PgaA. Maximal induction of PgaD and poly-GlcNAc synthesis requires the production of c-di-GMP by the dedicated diguanylate cyclase YdeH. Our results identify a novel regulatory mechanism that relies on ppGpp signalling to relay information about ribosomal performance to the Pga machinery, thereby inducing adhesin production and biofilm formation. Based on the important synergistic roles of ppGpp and c-di-GMP in this process, we suggest that interference with bacterial second messenger signalling might represent an effective means for biofilm control during chronic infections.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland. alexander.boehm@unibas.ch
authors.forename: Alex
authors.initials: A
authors.lastname: Boehm
authors.forename: Samuel
authors.initials: S
authors.lastname: Steiner
authors.forename: Franziska
authors.initials: F
authors.lastname: Zaehringer
authors.forename: Alain
authors.initials: A
authors.lastname: Casanova
authors.forename: Fabienne
authors.initials: F
authors.lastname: Hamburger
authors.forename: Daniel
authors.initials: D
authors.lastname: Ritz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Keck
authors.forename: Martin
authors.initials: M
authors.lastname: Ackermann
authors.forename: Tilman
authors.initials: T
authors.lastname: Schirmer
authors.forename: Urs
authors.initials: U
authors.lastname: Jenal
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000254:growth & development*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006159:Guanosine Tetraphosphate / Q000378:metabolism*; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012270:Ribosomes / Q000187:drug effects*; D015290:Second Messenger Systems; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D047071:beta-Glucans; C505465:poly-N-acetyl-1-6-glucosamine; D006159:Guanosine Tetraphosphate; C062025:bis(3',5')-cyclic diguanylic acid; C027627:guanosine-3',5'-bis(diphosphate) 3'-pyrophosphatase; D011755:Pyrophosphatases; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP