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Biofilm Inhibitor Taurolithocholic Acid Alters Colony Morphology, Specialized Metabolism, and Virulence of Pseudomonas aeruginosa.

ABSTRACT: Biofilm inhibition by exogenous molecules has been an attractive strategy for the development of novel therapeutics. We investigated the biofilm inhibitor taurolithocholic acid (TLCA) and its effects on the specialized metabolism, virulence, and biofilm formation of the clinically relevant bacterium Pseudomonas aeruginosa strain PA14. Our study shows that TLCA alters the specialized metabolism, thereby affecting P. aeruginosa colony biofilm physiology. We observed an upregulation of metabolites correlated to virulence such as the siderophore pyochelin. A wax moth virulence assay confirmed that treatment with TLCA increases the virulence of P. aeruginosa. On the basis of our results, we believe that future endeavors to identify biofilm inhibitors must consider how a putative lead alters the specialized metabolism of a bacterial community to prevent pathogens from entering a highly virulent state.

SUBMITTER: Condren AR

PROVIDER: S-EPMC7150652 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Biofilm inhibitor taurolithocholic acid alters colony morphology, specialized metabolism, and virulence of Pseudomonas aeruginosa

Project description:Tandem MS data used for GNPS networking and analysis. The samples included in this data set are fractions (A-G) from a bacterial extraction of PA14 with or without exposure to TLCA. There are also two controls: extractions from media exposed to TLCA and media alone. All fractions were analyzed in triplicate therefore each fraction has file raw files.

2018-12-18 | MSV000083258 | MassIVE

GNPS - Biofilm inhibitor taurolithocholic acid alters colony morphology, specialized metabolism, and virulence of Pseudomonas aeruginosa

2018-12-18 | MSV000083258 | GNPS

A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation.

Project description:Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited by mBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.

| S-EPMC3816427 | biostudies-literature

Glycoside hydrolase processing of the Pel polysaccharide alters biofilm biomechanics and Pseudomonas aeruginosa virulence.

Project description:Pel exopolysaccharide biosynthetic loci are phylogenetically widespread biofilm matrix determinants in bacteria. In Pseudomonas aeruginosa, Pel is crucial for cell-to-cell interactions and reducing susceptibility to antibiotic and mucolytic treatments. While genes encoding glycoside hydrolases have long been linked to biofilm exopolysaccharide biosynthesis, their physiological role in biofilm development is unclear. Here we demonstrate that the glycoside hydrolase activity of P. aeruginosa PelA decreases adherent biofilm biomass and is responsible for generating the low molecular weight secreted form of the Pel exopolysaccharide. We show that the generation of secreted Pel contributes to the biomechanical properties of the biofilm and decreases the virulence of P. aeruginosa in Caenorhabditis elegans and Drosophila melanogaster. Our results reveal that glycoside hydrolases found in exopolysaccharide biosynthetic systems can help shape the soft matter attributes of a biofilm and propose that secreted matrix components be referred to as matrix associated to better reflect their influence.

| S-EPMC9894940 | biostudies-literature

Colony-morphology screening uncovers a role for the Pseudomonas aeruginosa nitrogen-related phosphotransferase system in biofilm formation.

Project description:Pseudomonas aeruginosa is an opportunistic human pathogen whose survival is aided by forming communities known as biofilms, in which cells are encased in a self-produced matrix. We devised a mutant screen based on colony morphology to identify additional genes with previously unappreciated roles in biofilm formation. Our screen, which identified most known biofilm-related genes, also uncovered PA14_16550 and PA14_69700, deletions of which abrogated and augmented biofilm formation respectively. We also identified ptsP, which encodes enzyme I of the nitrogen-regulated phosphotransferase (PTS(Ntr)) system, as being important for cyclic-di-GMP production and for biofilm formation. Further experiments showed that biofilm formation is hindered in the absence of phosphotransfer through the PTS(Ntr), but only in the presence of enzyme II (PtsN), the putative regulatory module of the PTS(Ntr). These results implicate unphosphorylated PtsN as a negative regulator of biofilm formation and establish one of the first known roles of the PTS(Ntr) in P. aeruginosa.

| S-EPMC5130288 | biostudies-literature

Oxylipins produced by Pseudomonas aeruginosa promote biofilm formation and virulence.

Project description:The oxygenation of unsaturated fatty acids by dioxygenases occurs in all kingdoms of life and produces physiologically important lipids called oxylipins. The biological roles of oxylipins have been extensively studied in animals, plants, algae and fungi, but remain largely unidentified in prokaryotes. The bacterium Pseudomonas aeruginosa displays a diol synthase activity that transforms several monounsaturated fatty acids into mono- and di-hydroxylated derivatives. Here we show that oxylipins derived from this activity inhibit flagellum-driven motility and upregulate type IV pilus-dependent twitching motility of P. aeruginosa. Consequently, these oxylipins promote bacterial organization in microcolonies, increasing the ability of P. aeruginosa to form biofilms in vitro and in vivo (in Drosophila flies). We also demonstrate that oxylipins produced by P. aeruginosa promote virulence in Drosophila flies and lettuce. Our study thus uncovers a role for prokaryotic oxylipins in the physiology and pathogenicity of bacteria.

| S-EPMC5155153 | biostudies-literature

Quorum sensing modulates colony morphology through alkyl quinolones in Pseudomonas aeruginosa.

Project description:Acyl-homoserine lactone (acyl-HSL) and alkyl quinolone (AQ) based quorum-sensing (QS) systems are important for Pseudomonas aeruginosa virulence and biofilm formation. The effect of QS on biofilm formation is influenced by various genetic and environmental factors. Here, we used a colony biofilm assay to study the effect of the central acyl-HSL QS regulator, LasR, on biofilm formation and structure in the representative clinical P. aeruginosa isolate ZK2870.A lasR mutant exhibited wrinkled colony morphology at 37°C in contrast to the smooth colony morphology of the wild-type. Mutational analysis indicated that wrinkling of the lasR mutant is dependent on pel, encoding a biofilm matrix exopolysaccharide. Suppressor mutagenesis and complementation analysis implicated the AQ signaling pathway as the link between las QS and colony morphology. In this pathway, genes pqsA-D are involved in the synthesis of 4-hydroxyalkyl quinolines ("Series A congeners"), which are converted to 3,4-dihydroxyalkyl quinolines ("Series B congeners", including the well-characterized Pseudomonas Quinolone Signal, PQS) by the product of the LasR-dependent pqsH gene. Measurement of AQ in the wild-type, the lasR pqsA::Tn suppressor mutant as well as the defined lasR, pqsH, and lasR pqsH mutants showed a correlation between 4-hydroxyalkyl quinoline levels and the degree of colony wrinkling. Most importantly, the lasR pqsH double mutant displayed wrinkly morphology without producing any 3,4-dihydroxyalkyl quinolines. Constitutive expression of pqsA-D genes in a lasR pqsR::Tnmutant showed that colony wrinkling does not require the AQ receptor PqsR.Taken together, these results indicate that the las QS system represses Pel and modulates colony morphology through a 4-hydroxyalkyl quinoline in a PqsR-independent manner, ascribing a novel function to an AQ other than PQS in P. aeruginosa.

| S-EPMC3364869 | biostudies-other

Cobalt Complex with Thiazole-Based Ligand as New Pseudomonas aeruginosa Quorum Quencher, Biofilm Inhibitor and Virulence Attenuator.

Project description:Pseudomonas aeruginosa is one of the most dreaded human pathogens, because of its intrinsic resistance to a number of commonly used antibiotics and ability to form sessile communities (biofilms). Innovative treatment strategies are required and that can rely on the attenuation of the pathogenicity and virulence traits. The interruption of the mechanisms of intercellular communication in bacteria (quorum sensing) is one of such promising strategies. A cobalt coordination compound (Co(HL)?) synthesized from (E)-2-(2-(pyridin-2-ylmethylene)hydrazinyl)-4-(p-tolyl)thiazole (HL) is reported herein for the first time to inhibit P. aeruginosa 3-oxo-C12-HSL-dependent QS system (LasI/LasR system) and underling phenotypes (biofilm formation and virulence factors). Its interactions with a possible target, the transcriptional activator protein complex LasR-3-oxo-C12-HSL, was studied by molecular modeling with the coordination compound ligand having stronger predicted interactions than those of co-crystallized ligand 3-oxo-C12-HSL, as well as known-binder furvina. Transition metal group 9 coordination compounds may be explored in antipathogenic/antibacterial drug design.

| S-EPMC6099793 | biostudies-literature

Burkholderia cenocepacia ShvR-regulated genes that influence colony morphology, biofilm formation, and virulence.

Project description:Burkholderia cenocepacia is an opportunistic pathogen that primarily infects cystic fibrosis (CF) patients. Previously, we reported that ShvR, a LysR regulator, influences colony morphology, virulence, and biofilm formation and regulates the expression of an adjacent 24-kb genomic region encoding 24 genes. In this study, we report the functional characterization of selected genes in this region. A Tn5 mutant with shiny colony morphology was identified with a polar mutation in BCAS0208, predicted to encode an acyl-coenzyme A dehydrogenase. Mutagenesis of BCAS0208 and complementation analyses revealed that BCAS0208 is required for rough colony morphology, biofilm formation, and virulence on alfalfa seedlings. It was not possible to complement with BCAS0208 containing a mutation in the catalytic site. BCAS0201, encoding a putative flavin adenine dinucleotide (FAD)-dependent oxidoreductase, and BCAS0207, encoding a putative citrate synthase, do not influence colony morphology but are required for optimum levels of biofilm formation and virulence. Both BCAS0208 and BCAS0201 contribute to pellicle formation, although individual mutations in each of these genes had no appreciable effect on pellicle formation. A mutant with a polar insertion in BCAS0208 was significantly less virulent in a rat model of chronic lung infection as well as in the alfalfa model. Genes in this region were shown to influence utilization of branched-chain fatty acids, tricarboxylic acid cycle substrates, l-arabinose, and branched-chain amino acids. Together, our data show that the ShvR-regulated genes BCAS0208 to BCAS0201 are required for the rough colony morphotype, biofilm and pellicle formation, and virulence in B. cenocepacia.

| S-EPMC3147549 | biostudies-literature

Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.

Project description:Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.

| S-EPMC2246019 | biostudies-literature

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