In vitro activity of taurolidine gel on bacteria associated with periodontitis.

OBJECTIVES The purpose of this in vitro study was to determine the antimicrobial activity of two different taurolidine gel formulations in comparison with minocycline microspheres. METHODS Three percent taurolidine gel (TLG3) and 2 % taurolidine gel (TLG2) were compared to minocycline microspheres (MINO) against single bacterial species and a 12-species-mixture. The antimicrobial activity was proven by determination of minimal inhibitory concentrations (MICs), killing assays, after exposure of the antimicrobials as well as within a biofilm. RESULTS The MICs against the single species were between 0.5 and 2 mg/ml of taurolidine. MICs of the used mixed microbiota were 1.5 mg/ml (TLG3) and 4 mg/ml (TLG2). Fusobacterium nucleatum and Porphyromonas gingivalis were completely killed by 10 % TLG3 and TLG2 (equivalent to 3 and 2 mg/ml taurolidine) after 6 h. The mixture of 12 species was not completely killed by any of the test substances. Taurolidine gels showed a post-antimicrobial activity, however being less than that of MINO. On biofilms, taurolidine gels reduced concentration dependently the colony forming unit (CFU) counts (multi-species biofilms by 3.63 log10 after 100 % (30 mg/ml) of TLG3), reductions were 2.12 log10 after MINO (1000 μg/ml minocycline). CONCLUSIONS Taurolidine gel formulations exert antimicrobial activity against bacteria associated with periodontal disease. Nevertheless, a complete elimination of biofilms seems to be impossible and underlines the importance of mechanical removal of biofilms prior to application of the antimicrobial. CLINICAL RELEVANCE Taurolidine gels may represent a potential alternative for adjunctive topical antimicrobial treatment in periodontitis and infectious peri-implant diseases

Taurolidine Acts on Bacterial Virulence Factors and Does Not Induce Resistance in Periodontitis-Associated Bacteria-An In-Vitro Study.

The aims of the present study were: (a) to determine the mechanism of action of taurolidine against bacterial species associated with periodontal disease, and (b) to evaluate the potential development of resistance against taurolidine as compared with minocycline. After visualizing the mode of action of taurolidine by transmission electron micrographs, the interaction with most important virulence factors (lipopolysaccharide (LPS), Porphyromonas gingivalis gingipains, Aggregatibacter actinomycetemcomitans leukotoxin), was analyzed. Then, 14 clinical isolates from subgingival biofilm samples were transferred on agar plates containing subinhibitory concentrations of taurolidine or minocycline up to 50 passages. Before and after each 10 passages, minimal inhibitory concentrations (MICs) were determined. Increasing MICs were screened for efflux mechanism. Taurolidine inhibited in a concentration-dependent manner the activities of LPS and of the arginine-specific gingipains; however, an effect on A.actinomycetemcomitans leukotoxin was not detected. One P.gingivalis strain developed a resistance against taurolidine, which was probably linked with efflux mechanisms. An increase of MIC values of minocycline occurred in five of the 14 included strains after exposure to subinhibitory concentrations of the antibiotic. The present results indicate that: a) taurolidine interacts with LPS and gingipains, and b) development of resistance seems to be a rare event when using taurolidine

Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation

AbstractTruncation mutations in the adenomatous polyposis coli protein (APC) are responsible for familial polyposis, a form of inherited colon cancer. In addition to its role in mediating β-catenin degradation in the Wnt signaling pathway, APC plays a role in regulating microtubules. This was suggested by its localization to the end of dynamic microtubules in actively migrating areas of cells and by the apparent correlation between the dissociation of APC from polymerizing microtubules and their subsequent depolymerization [1, 2]. The microtubule binding domain is deleted in the transforming mutations of APC [3, 4]; however, the direct effect of APC protein on microtubules has never been examined. Here we show that binding of APC to microtubules increases microtubule stability in vivo and in vitro. Deleting the previously identified microtubule binding site from the C-terminal domain of APC does not eliminate its binding to microtubules but decreases the ability of APC to stabilize them significantly. The interaction of APC with microtubules is decreased by phosphorylation of APC by GSK3β. These data confirm the hypothesis that APC is involved in stabilizing microtubule ends. They also suggest that binding of APC to microtubules is mediated by at least two distinct sites and is regulated by phosphorylation

The well-being of Swiss general internal medicine residents

Physician well-being has an impact on productivity and quality of care. Residency training is a particularly stressful period

Discovery of Highly Potent and Selective CXCR4 Inhibitors Using Protein Epitope Mimetics (PEM) Technology

Novel, highly potent CXCR4 inhibitors with good pharmacokinetic properties were obtained by applying PEM technology starting from the naturally occurring ?-hairpin peptide polyphemusin II. The design involved incorporation of key residues from polyphemusin II into a macrocyclic template-bound ?-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized, resulting in CXCR4 inhibitors such as POL2438 and POL3026. Their activities were confirmed in a series of in vitro HIV-1 infection assays. Besides high selectivity for CXCR4, POL3026 had excellent plasma stability and favorable pharmacokinetic properties in dogs. In a murine model POL3026 was highly efficacious in hematopoietic stem cell mobilization. Hence, PEM-based CXCR4 inhibitors have the potential to become therapeutic agents for the treatment of HIV infections (as entry inhibitor), cancer (e.g. for inhibition of metastasis), stem cell transplant and inflammation

Lack of Adenomatous Polyposis Coli Protein Correlates with a Decrease in Cell Migration and Overall Changes in Microtubule Stability

Most sporadic colorectal tumors carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein is involved in many processes that govern gut tissue. In addition to its involvement in the regulation of β-catenin, APC is a cytoskeletal regulator with direct and indirect effects on microtubules. Cancer-related truncation mutations lack direct and indirect binding sites for microtubules in APC, suggesting that loss of this function contributes to defects in APC-mutant cells. In this study, we show that loss of APC results in disappearance of cellular protrusions and decreased cell migration. These changes are accompanied by a decrease in overall microtubule stability and also by a decrease in posttranslationally modified microtubules in the cell periphery particularly the migrating edge. Consistent with the ability of APC to affect cell shape, the overexpression of APC in cells can induce cellular protrusions. These data demonstrate that cell migration and microtubule stability are linked to APC status, thereby revealing a weakness in APC-deficient cells with potential therapeutic implications