Characterization of Nutrient-Induced Dispersion in
            <i>Pseudomonas aeruginosa</i>
            PAO1 Biofilm

Sauer, Karin; Cullen, M.; Rickard, Alexander H.; Zeef, Leo; Davies, David G.; Gilbert, Peter

doi:10.1128/jb.186.21.7312-7326.2004

Cited by 430 publications

(443 citation statements)

References 67 publications

(101 reference statements)

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“…2). We showed that dispersed cells are in a distinct stage in the transition from biofilm to planktonic lifestyle, as supported by the evidence showing that biofilm cells differ from dispersed cells 15 . We identified multiple T2SS genes, such as PA3820 (secF) and PA3821 (secD), that were Pyoverdine RFU/OD600 Pyoverdine RFU/OD600…”

Section: Dispersed Cells Represent a Distinct Stage Of Bacterial Lifesupporting

confidence: 55%

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Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles

et al. 2014

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Bacteria assume distinct lifestyles during the planktonic and biofilm modes of growth. Increased levels of the intracellular messenger c-di-GMP determine the transition from planktonic to biofilm growth, while a reduction causes biofilm dispersal. It is generally assumed that cells dispersed from biofilms immediately go into the planktonic growth phase. Here we use single-nucleotide resolution transcriptomic analysis to show that the physiology of dispersed cells from Pseudomonas aeruginosa biofilms is highly different from those of planktonic and biofilm cells. In dispersed cells, the expression of the small regulatory RNAs RsmY and RsmZ is downregulated, whereas secretion genes are induced. Dispersed cells are highly virulent against macrophages and Caenorhabditis elegans compared with planktonic cells. In addition, they are highly sensitive towards iron stress, and the combination of a biofilm-dispersing agent, an iron chelator and tobramycin efficiently reduces the survival of the dispersed cells.

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Section: Dispersed Cells Represent a Distinct Stage Of Bacterial Lifesupporting

confidence: 55%

“…The active process of dispersing cells is specific and regulated, in contrast to mechanical and passive dispersal, which involves sloughing off biofilm cells. While it is common knowledge that biofilm cells differ from dispersed cells 15 , it is unclear whether biofilm-dispersed cells are similar to planktonic cells with respect to their physiology.…”

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confidence: 99%

Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles

et al. 2014

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“…Biofilm dispersion can be induced by a variety of environmental cues, including changes in growth medium composition, pH, oxygen, and carbon concentrations, exposure to heavy metals and nitric oxide, exposure to the polysaccharide degrading enzyme dispersin B, and self-synthesized signaling molecules such as cis-2-decenoic acid (1)(2)(3)(4)(5)(6)(7)(8)(9). Dispersed cells are characterized by distinct gene expression and protein production patterns and increased susceptibility to antimicrobial agents compared with their sessile counterparts (2,(10)(11)(12). Moreover, although biofilms are considered the root cause of chronic and persistent infections (13), biofilm dispersion may be part of an inherent strategy of Pseudomonas aeruginosa to initiate a disseminating phenotype, causing acute and periodic infections.…”

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confidence: 99%

“…Regulation of biofilm dispersion has also been linked to the modulation of the intracellular signaling molecule cyclic di-GMP (c-di-GMP), high levels of which promote sessile growth, and low levels correlate with planktonic existence. Several proteins associated with dispersion have been shown to possess cdi-GMP-modulating activity (1)(2)(3)(4)14). These include the phosphodiesterases (PDEs) RbdA and DipA, which promote the return to free-swimming growth by reducing cellular c-di-GMP levels (15,16).…”

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confidence: 99%

Dispersion by Pseudomonas aeruginosa requires an unusual posttranslational modification of BdlA

Petrova

Sauer

2012

Proc. Natl. Acad. Sci. U.S.A.

124

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Dispersion enables biofilm bacteria to transit from the biofilm to the planktonic growth state and to spawn novel communities in new locales. Although the chemotaxis protein BdlA plays a role in the dispersion of Pseudomonas aeruginosa biofilms in response to environmental cues, little is known about regulation of BdlA activity or how BdlA modulates the dispersion response. Here, we demonstrate that BdlA in its native form is inactive and is activated upon nonprocessive proteolysis at a ClpP-protease-like cleavage site located between the Per Arnt Sim (PAS) sensory domains PASa and PASb. Activation of BdlA to enable biofilm dispersion requires phosphorylation at tyrosine-238 as a signal, elevated c-di-GMP levels, the chaperone ClpD, and the protease ClpP. The resulting truncated BdlA polypeptide chains directly interact and are required for P. aeruginosa biofilms to disperse. Our results provide a basis for understanding the mechanism of biofilm dispersion that may be applicable to a large number of biofilm-forming pathogenic species. Insights into the mechanism of BdlA function have implications for the control of biofilm-related infections.

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“…[17][18][19] Furthermore, modulation of c-di-GMP signaling by environmental changes has also been linked with the dispersion of cells from established biofilms. [20][21][22] Therefore, drugs able to inhibit c-di-GMP synthesis are promising candidates for new anti-microbial agents with anti-biofilm activity. Indeed, genetic manipulation of c-di-GMP levels through the modulation of PDE activity in P. aeruginosa prevented and promoted clearance of biofilm infections in mice.…”

Section: Introductionmentioning

confidence: 99%

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

Wiggers¹,

Crusca²,

Silva³

et al. 2017

J. Braz. Chem. Soc.

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Biofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand-and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy.Keywords: c-di-GMP, diguanylate cyclase enzymes, bacterial biofilm, virtual screening, drug repositioning IntroductionBacterial biofilms, a multicellular community encased in an extracellular matrix, are commonly related to persistent infections, usually less susceptible to antibiotic treatments when compared to planktonic cells. [1][2][3] According to the National Institute of Health, 4 up to 80% of human bacterial infections involve biofilm-associated microorganisms. For instance, biofilm formation plays a crucial role in microbe pathogenicity such as Legionnaire's disease, endocarditis, pneumonia accompanied by cystic fibrosis and infections of urogenital and gastrointestinal tracts. 5,6 Furthermore, biofilm infections promote devastating effects on medical device implanted and immunocompromised individuals, representing a major medical and economic predicament. 7 The burden on public health due to chronic biofilm contaminations urge for the development of new chemotherapeutic approaches. Cellular processes controlling biofilm formation and dispersion, such as quorum sensing systems and metabolic pathways, are important targets for the discovery of new bioactive compounds. 8-10The second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a key regulator of bacterial behavior, especially controlling the switch between the motile planktonic and sedentary biofilm-associated lifestyles. Cyclic di-GMP stimulates the biosynthesis of adhesins and exopolysaccharide matrix substances in biofilms and inhibits various forms of motility. In general, low intracellular c-di-GMP levels are associated with freeswimming cells, whereas bacter...

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Characterization of Nutrient-Induced Dispersion in Pseudomonas aeruginosa PAO1 Biofilm

Cited by 430 publications

References 67 publications

Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles

Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles

Dispersion by Pseudomonas aeruginosa requires an unusual posttranslational modification of BdlA

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

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