The Hunger Games: Exploits Human Neutrophils As an Epinephrine Source for Survival.

is a gram-negative facultative anaerobe and an opportunistic oral pathogen, strongly associated with periodontitis and other inflammatory diseases. Periodontitis is a chronic inflammation of the periodontium resulting from the inflammatory response of the host towards the dysbiotic microbial community present at the gingival crevice. Previously, our group identified catecholamines and iron as the signals that activate the QseBC two-component system in , necessary for the organism to acquire iron as a nutrient to survive in the anaerobic environment.

Assessment of CafA Targeted BAR-Encapsulated Nanoparticles against Oral Biofilms.

adherence to is a crucial initial event that facilitates the colonization of , a key pathogen in periodontal disease. As such, blocking these early interactions may present a potential avenue to limit colonization. Nanoparticles encapsulating a synthetic peptide BAR (BAR-encapsulated NPs) inhibit / biofilm formation 1.

Identification of Small-Molecule Inhibitors Targeting Porphyromonas gingivalis Interspecies Adherence and Determination of Their and Efficacies.

is one of the primary causative agents of periodontal disease and initially colonizes the oral cavity by adhering to commensal streptococci. Adherence requires the interaction of a minor fimbrial protein (Mfa1) of with streptococcal antigen I/II (AgI/II). Our previous work identified an AgI/II peptide that potently inhibited adherence and significantly reduced virulence , suggesting that this interaction represents a potential target for drug discovery.

Rapid Release Polymeric Fibers for Inhibition of Adherence to .

Active agents targeting key bacterial interactions that initiate biofilm formation in the oral cavity, may alter periodontitis progression; however, to date, specifically-targeted prophylactic and treatment strategies have been limited. Previously we developed a peptide, BAR (SspB Adherence Region), that inhibits oral biofilm formation and , and BAR nanoparticles that increase BAR effectiveness via multivalency and prolonged delivery. However, limited BAR loading and nanoparticle retention in the oral cavity can result in inadequate release and efficaciousness.

Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci.

Porphyromonas gingivalis is associated with chronic periodontitis and may initially colonize the oral cavity by adhering to streptococci. Adhesion to streptococci is driven by interaction of the minor fimbrial antigen (Mfa1) with streptococcal antigen I/II. We identified the region of antigen I/II required for this interaction and developed small molecule mimetics that inhibited P.

Peptide and non-peptide mimetics as potential therapeutics targeting oral bacteria and oral biofilms.

The development of the oral biofilm requires a complex series of interactions between host tissues and the colonizing bacteria as well as numerous interspecies interactions between the organisms themselves. Disruption of normal host-microbe homoeostasis in the oral cavity can lead to a dysbiotic microbial community that contributes to caries or periodontal disease. A variety of approaches have been pursued to develop novel potential therapeutics that are active against the oral biofilm and/or target specific oral bacteria.

'Second-generation' 1,2,3-triazole-based inhibitors of adherence to oral streptococci and biofilm formation.

Several 'second-generation' click inhibitors of the multi-species biofilm propagated by the adherence of the oral pathogen to were synthesized and evaluated. The design of the structures was based on the results obtained with the first-generation diphenyloxazole 'click' inhibitors which bear suitable hydrophobic and polar groups within a dual scaffold molecule bearing a 1,2,3-triazole spacer. The structures of the synthetic targets reported herein now consist of a triazolyl(phenylsulfonylmethyl) and a triazolyl(phenylsulfinylmethyl) spacer which joins a 4,5-diphenyloxazole with both phenyl rings bearing lipophilic substituents.

Functional assessment of peptide-modified PLGA nanoparticles against oral biofilms in a murine model of periodontitis.

The interaction of the periodontal pathogen Porphyromonas gingivalis (Pg) with commensal streptococci promotes Pg colonization of the oral cavity. Previously, we demonstrated that a peptide (BAR) derived from Streptococcus gordonii (Sg) potently inhibited adherence of Pg to streptococci and reduced Pg virulence in a mouse model of periodontitis. Thus, BAR may represent a novel therapeutic to control periodontitis by preventing Pg colonization of the oral cavity.

BAR-encapsulated nanoparticles for the inhibition and disruption of Porphyromonas gingivalis-Streptococcus gordonii biofilms.

Background: Porphyromonas gingivalis adherence to oral streptococci is a key point in the pathogenesis of periodontal diseases (Honda in Cell Host Microbe 10:423-425, 2011). Previous work in our groups has shown that a region of the streptococcal antigen denoted BAR (SspB Adherence Region) inhibits P. gingivalis/S.

and Activity of Peptidomimetic Compounds That Target the Periodontal Pathogen Porphyromonas gingivalis.

The interaction of the periodontal pathogen with oral streptococci is important for initial colonization of the oral cavity by and is mediated by a discrete motif of the streptococcal antigen I/II protein. A synthetic peptide encompassing this motif functions as a potent inhibitor of adherence, but the use of peptides as topically applied therapeutic agents in the oral cavity has limitations arising from the relatively high cost of peptide synthesis and their susceptibility to degradation by proteases expressed by oral organisms. In this study, we demonstrate the and activity of five small-molecule mimetic compounds of the streptococcal peptide.

Peptide-modified nanoparticles inhibit formation of biofilms with .

Purpose: The interaction of g with commensal streptococci promotes colonization of the oral cavity. We previously showed that a synthetic peptide (BAR) derived from potently inhibited the formation of biofilms (IC =1.3 µM) and reduced virulence in a mouse model of periodontitis.

Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.

Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C.

1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation.

The development and use of small-molecule inhibitors of the adherence of Porphyromonas gingivalis to oral streptococci represents a potential therapy for the treatment of periodontal disease as these organisms work in tandem to colonize the oral cavity. Earlier work from these laboratories demonstrated that a small synthetic peptide was an effective inhibitor of the interaction between P. gingivalis and Streptococcus gordonii and that a small-molecule peptidomimetic would provide a more stable, less expensive and more effective inhibitor.

Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds.

New routes to 2, 4, 5-trisubstituted oxazoles were established whereby the substitution pattern was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-disubstituted oxazoles were prepared by refinements of an earlier described process whereby chloroacetyl esters of symmetrical and non-symmetrical acyloins were cyclized using an ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then installed by substitution under mild conditions.

Transcriptional regulation of the Aggregatibacter actinomycetemcomitans ygiW-qseBC operon by QseB and integration host factor proteins.

The QseBC two-component system plays a pivotal role in regulating virulence and biofilm growth of the oral pathogen Aggregatibacter actinomycetemcomitans. We previously showed that QseBC autoregulates the ygiW-qseBC operon. In this study, we characterized the promoter that drives ygiW-qseBC expression.

Integration host factor is required for replication of pYGK-derived plasmids in Aggregatibacter actinomycetemcomitans.

In this study, we show that integration host factor protein (IHF) is required for replication of pYGK plasmids in Aggregatibacter actinomycetemcomitans. YGK plasmids were not replicated in A. actinomycetemcomitans strains lacking either the α- or β- subunit of IHF.

Differential transcriptional regulation of Aggregatibacter actinomycetemcomitans lsrACDBFG and lsrRK operons by integration host factor protein.

We previously showed that the Aggregatibacter actinomycetemcomitans lsrACDBFG and lsrRK operons are regulated by LsrR and cyclic AMP receptor protein (CRP) and that proper regulation of the lsr locus is required for optimal biofilm growth by A. actinomycetemcomitans. Here, we identified sequences that reside immediately upstream from both the lsrA and lsrR start codons that closely resemble the consensus recognition sequence of Escherichia coli integration host factor (IHF) protein.

Altered antigenic profiling and infectivity of Porphyromonas gingivalis in smokers and non-smokers with periodontitis.

Background: Cigarette smokers are more susceptible to periodontal diseases and are more likely to be infected with Porphyromonas gingivalis than non-smokers. Furthermore, smoking is known to alter the expression of P. gingivalis surface components and compromise immunoglobulin (Ig)G generation.

ygiW and qseBC are co-expressed in Aggregatibacter actinomycetemcomitans and regulate biofilm growth.

The quorum-sensing Escherichia coli regulators B and C (QseBC) two-component system were previously shown to regulate biofilm growth of the oral pathogen Aggregatibacter actinomycetemcomitans and to be essential for virulence. In this study, we use RT-PCR to show that an open reading frame, ygiW, residing upstream of qseBC and encoding a hypothetical protein is co-expressed with qseBC. In addition, using a series of lacZ transcriptional fusion constructs and 5'-rapid amplification of cDNA Ends (RACE), the promoter that drives expression of the ygiW-qseBC operon and the transcriptional start site was mapped to the 372 bp intergenic region upstream from ygiW.

Transcriptional regulation of Aggregatibacter actinomycetemcomitans lsrACDBFG and lsrRK operons and their role in biofilm formation.

Autoinducer-2 (AI-2) is required for biofilm formation and virulence of the oral pathogen Aggregatibacter actinomycetemcomitans, and we previously showed that lsrB codes for a receptor for AI-2. The lsrB gene is expressed as part of the lsrACDBFG operon, which is divergently transcribed from an adjacent lsrRK operon. In Escherichia coli, lsrRK encodes a repressor and AI-2 kinase that function to regulate lsrACDBFG.

Preparation of azidoaryl- and azidoalkyloxazoles for click chemistry.

A series of azidoaryl- and azidoalkyl(diphenyl)oxazole scaffolds were warranted for biofilm inhibition studies. Cyclization of azidoaryl- or azidoalkyl esters of benzoin with ammonium acetate in acetic acid gives 2-azidoaryl- or 2-azidoalkyl-4,5-diphenyloxazoles. The azidoaryl esters are prepared from the corresponding azidocarboxylic acids/acid chlorides while the azidoalkyl esters are prepared from the corresponding haloalkyl esters.

Deep sequencing of Porphyromonas gingivalis and comparative transcriptome analysis of a LuxS mutant.

Porphyromonas gingivalis is a major etiological agent in chronic and aggressive forms of periodontal disease. The organism is an asaccharolytic anaerobe and is a constituent of mixed species biofilms in a variety of microenvironments in the oral cavity. P.

Tobacco smoke augments Porphyromonas gingivalis-Streptococcus gordonii biofilm formation.

Smoking is responsible for the majority of periodontitis cases in the US and smokers are more susceptible than non-smokers to infection by the periodontal pathogen Porphyromonas gingivalis. P. gingivalis colonization of the oral cavity is dependent upon its interaction with other plaque bacteria, including Streptococcus gordonii.

Community signalling between Streptococcus gordonii and Porphyromonas gingivalis is controlled by the transcriptional regulator CdhR.

Interspecies signalling between Porphyromonas gingivalis and Streptococcus gordonii serves to constrain development of dual species communities. Contact with S. gordonii propagates a tyrosine phosphorylation-dependent signal within P.