Biology subjects

Taudte, N.

Publications and source records attributed to Taudte, N..

4 recordsLinked to original sources

bioRxiv2025

Effect of a bacterial Glutaminyl Cyclase inhibitor on multi-species-biofilms

Modifying bacterial virulence could be an interesting alternative to antibiotics. The study aimed to examine the effects of an inhibitor targeting bacterial glutaminyl cyclase (which is selectively present in Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), and Prevotella intermedia (Pi)) on various multispecies biofilms. Two multi-species biofilms--one containing four species (including Tf) and another with 12 species (including Tf, Pg, and Pi)--were cultured in the presence of 31.25-500 {micro}M of a [4,5-c]pyridine-based inhibitor. After 24 hours, bacterial counts, biofilm mass, metabolic activity, and, when Pg was included, Arg-gingipain activity were measured. Additionally, the biofilms were exposed to monocytic cells; here, the release of interleukin (IL)-1{beta} and IL-10 was analyzed. The data were analyzed using a one-way analysis of variance (ANOVA) with a post-hoc comparison performed using the Bonferroni correction. In all biofilms, total bacterial counts and those of Pg and Tf remained unaffected by the inhibitor. In the 12-species biofilm, both mass" and total metabolic activity decreased at high inhibitor concentrations (500 {micro}M to 75.2{+/-}6.5% and 87.2{+/-}5.8%, respectively; each p<0.001). The arginine-specific amidolytic activities of Rgp declined dose-dependently, down to 60.4{+/-}10.2% (p<0.001) at 500 {micro}M of the inhibitor. Consequently, Pg colonies lost pigmentation as inhibitor concentrations increased. The inhibitor also reduced IL-1{beta} release from monocytic cells stimulated by the 12-species biofilm. The studied [4,5-c]pyridine-based inhibitor is able to modify virulence of a multispecies biofilm. It might have the potential to be a promising approach in periodontal prevention and therapy.

microbiology↗

bioRxiv2025

Novel small molecule targeting PgQC reduces Porphyromonas gingivalis virulence

Periodontitis, a chronic inflammatory disease affecting the periodontium, is primarily driven by dysbiotic of the oral microbiome with Porphyromonas gingivalis as a keystone pathogen. Current therapeutic approaches rely on mechanical debridement and antimicrobials, which face limitations including antibiotic resistance and microbiome disruption. Pathoblockers represent a novel therapeutic strategy that selectively targets virulence factors without bactericidal effects, potentially reducing resistance development while preserving beneficial microbiota. Here, we describe the characterization of S-0636, a novel reversible inhibitor of zinc-dependent glutaminyl cyclase (PgQC), as a compound to selectively suppress growth of P. gingivalis. The compounds effects was assessed through enzymatic assays, bacterial growth studies, virulence factor activity measurements (gingipain activity, hemagglutination, keratinocyte invasion), selectivity testing against commensal oral bacteria, resistance development analysis over 50 passages, and cytotoxicity evaluation in human cell lines. S-0636 demonstrated potent PgQC inhibition with a Ki value of 0.014 M and has successfully reduced the intracellular PgQC activity by 50% at 8 M and had no bactericidal effects. Treatment of P. gingivalis with S-0636 significantly decreased gingipain activity, impaired hemagglutination capacity, and reduced keratinocyte invasion by 76% at 62.5 M. The compound showed high selectivity, with no growth inhibition of ten tested oral commensal species at concentrations up to 0.25 mM. Importantly, no resistance development was observed after 50 bacterial passages, and cytotoxicity remained minimal in human cell lines with >80% viability at 0.5 mM. In previous studies, PgQC was suggested as an enzyme responsible for pGlu-modification and stabilization of bacterial virulence factors. The current study now validates PgQC as an attractive target for pathoblocker development, demonstrating that S-0636 effectively attenuates P. gingivalis pathogenicity through selective virulence factor inhibition while preserving bacterial viability and oral microbiome integrity. The absence of resistance development and low cytotoxicity profile support the potential clinical translation of this approach for periodontal disease management, representing a promising alternative to conventional antimicrobial therapies.

microbiology↗

bioRxiv2025

Infection-Specific Reprogramming of Microglia Reveals Distinct Virulence Pathways Linking Periodontal Pathogens to Alzheimer's Disease

Microglial dysregulation is increasingly recognized as a driver of Alzheimers disease (AD), yet how pathogen-specific cues sculpt microglial diversity remains unclear. Here we integrate high-dimensional single-cell cytometry in vitro with spatial proteomics in vivo to dissect the impact of two major periodontal pathogens on microglia. Using a 36-marker CyTOF panel, we exposed SIM-A9 microglia to wild-type Porphyromonas gingivalis (Pg) or Tannerella forsythia (Tf) and to gingipain-deficient or S-layer-deficient mutants, resolving 38 clusters. Virulence-factor "switches" redirected cells from homeostatic states toward i) oxidative, antigen-presenting programmes driven by Pg gingipains and ii) an immunosuppressive, exhausted-like state driven by the Tf S-layer. Complementary 37-marker imaging mass cytometry of 5xFAD x hTau knock-in mice chronically infected with Pg identified 21 microglial subclusters. The cortex--but not hippocampus--lost two Arg1/IL-10 immunoregulatory subsets (>2-fold decrease) while NADPH-oxidase-high microglia accumulated around amyloid-{beta} and tau aggregates. These data demonstrate pathogen-specific reprogramming of microglia across model systems and brain regions, linking virulence-factor activity to AD-relevant neuroinflammation. By pinpointing gingipains and the bacterial S-layer as molecular "switches," our study highlights tractable therapeutic targets for limiting infection-driven microglial dysfunction in Alzheimers disease.

neuroscience↗

bioRxiv2021

Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer's disease-like mice

Pyroglutamate-3 amyloid-{beta} (pGlu3 A{beta}) is an N-terminally modified, toxic form of amyloid-{beta} that is present in cerebral amyloid plaques and vascular deposits. Using the Fc-competent murine anti-pGlu3 A{beta} monoclonal antibody (mAb), 07/2a, we present here a nonpharmacological approach using focused ultrasound (FUS) with intravenous (i.v.) injection of microbubbles (MB) to facilitate i.v. delivery of the 07/2a mAb across the blood brain barrier (BBB) in order to improve A{beta} removal and restore memory in aged APP/PS1 mice, an Alzheimers disease (AD)-like model of amyloidogenesis. Compared to sham-treated controls, aged APP/PS1 mice treated with 07/2a immediately prior to FUS-mediated BBB disruption (mAb + FUS-BBBD combination treatment) showed significantly better spatial learning and memory in the Water T Maze. FUS-BBBD treatment alone improved contextual fear learning and memory in aged WT and APP/PS1 mice, respectively. APP/PS1 mice given the combination treatment had reduced A{beta}42 and pGlu3 A{beta} hippocampal plaque burden compared to PBS-treated APP/PS1 mice. Hippocampal synaptic puncta density and synaptosomal synaptic protein levels were also higher in APP/PS1 mice treated with 07/2a just prior to BBB disruption. Increased Iba-1+ microglia were observed in the hippocampi of AD mice treated with 07/2a with and without FUS-BBBD, and APP/PS1 mice that received hippocampal BBB disruption and 07/2a showed increased Ly6G+ monocytes in hippocampal CA3. FUS-induced BBB disruption did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment. Our findings suggest that FUS is useful tool that may enhance delivery of an anti-pGlu3 A{beta} mAb for immunotherapy. FUS-mediated BBB disruption in combination with the 07/2a mAb also appears to facilitate monocyte infiltration in this AD model. Overall, these effects resulted in greater sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS as a noninvasive method to increase the therapeutic efficacy in AD patients.

bioengineering↗