@phdthesis{Reimer2017,
  author    = {Reimer, Anastasija},
  title     = {Search for novel antimicrobials against \(Neisseria\) \(gonorrhoeae\) and \(Chlamydia\) \(trachomatis\)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143168},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2017},
  abstract  = {The obligate human pathogen Neisseria gonorrhoeae is responsible for the widespread sexually transmitted disease gonorrhoea, which in rare cases also leads to the development of disseminated gonococcal infection (DGI). DGI is mediated by PorBIA-expressing bacteria that invade host cells under low phosphate condition by interaction with the scavenger receptor-1 (SREC-I) expressed on the surface of endothelial cells. The interaction of PorBIA and SREC-I was analysed using different in vitro approaches, including surface plasmon resonance experiments that revealed a direct phosphate-independent high affinity interaction of SREC-I to PorBIA. However, the same binding affinity was also found for the other allele PorBIB, which indicates unspecific binding and suggests that the applied methods were unsuitable for this interaction analysis. Since N. gonorrhoeae was recently classified as a "super-bug" due to a rising number of antibiotic-resistant strains, this study aimed to discover inhibitors against the PorBIA-mediated invasion of N. gonorrhoeae. Additionally, inhibitors were searched against the human pathogen Chlamydia trachomatis, which causes sexually transmitted infections as well as infections of the upper inner eyelid. 68 compounds, including plant-derived small molecules, extracts or pure compounds of marine sponges or sponge-associated bacteria and pipecolic acid derivatives, were screened using an automated microscopy based approach. No active substances against N. gonorrhoeae could be identified, while seven highly antichlamydial compounds were detected. The pipecolic acid derivatives were synthesized as potential inhibitors of the virulence-associated "macrophage infectivity potentiator" (MIP), which exhibits a peptidyl prolyl cis-trans isomerase (PPIase) enzyme activity. This study investigated the role of C. trachomatis and N. gonorrhoeae MIP during infection. The two inhibitors PipN3 and PipN4 decreased the PPIase activity of recombinant chlamydial and neisserial MIP in a dose-dependent manner. Both compounds affected the chlamydial growth and development in epithelial cells. Furthermore, this work demonstrated the contribution of MIP to a prolonged survival of N. gonorrhoeae in the presence of neutrophils, which was significantly reduced in the presence of PipN3 and PipN4. SF2446A2 was one of the compounds that had a severe effect on the growth and development of C. trachomatis. The analysis of the mode of action of SF2446A2 revealed an inhibitory effect of the compound on the mitochondrial respiration and mitochondrial ATP production of the host cell. However, the chlamydial development was independent of proper functional mitochondria, which excluded the connection of the antichlamydial properties of SF2446A2 with its inhibition of the respiratory chain. Only the depletion of cellular ATP by blocking glycolysis and mitochondrial respiratory chain inhibited the chlamydial growth. A direct effect of SF2446A2 on C. trachomatis was assumed, since the growth of the bacteria N. gonorrhoeae and Staphylococcus aureus was also affected by the compound. In summary, this study identified the severe antichlamydial activity of plant-derived naphthoquinones and the compounds derived from marine sponges or sponge-associated bacteria SF2446A2, ageloline A and gelliusterol E. Furthermore, the work points out the importance of the MIP proteins during infection and presents pipecolic acid derivatives as novel antimicrobials against N. gonorrhoeae and C. trachomatis.},
  subject      = {Neisseria gonorrhoeae},
  language  = {en}
}
@article{RadakovicReboredoHelmetal.2017,
  author    = {Radakovic, D. and Reboredo, J. and Helm, M. and Weigel, T. and Sch{\"u}rlein, S. and Kupczyk, E. and Leyh, R. G. and Walles, H. and Hansmann, J.},
  title     = {A multilayered electrospun graft as vascular access for hemodialysis},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0185916},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159102},
  pages     = {e0185916},
  year      = {2017},
  abstract  = {Despite medical achievements, the number of patients with end-stage kidney disease keeps steadily raising, thereby entailing a high number of surgical and interventional procedures to establish and maintain arteriovenous vascular access for hemodialysis. Due to vascular disease, aneurysms or infection, the preferred access—an autogenous arteriovenous fistula—is not always available and appropriate. Moreover, when replacing small diameter blood vessels, synthetic vascular grafts possess well-known disadvantages. A continuous multilayered gradient electrospinning was used to produce vascular grafts made of collagen type I nanofibers on luminal and adventitial graft side, and poly-ɛ-caprolactone as medial layer. Therefore, a custom-made electrospinner with robust environmental control was developed. The morphology of electrospun grafts was characterized by scanning electron microscopy and measurement of mechanical properties. Human microvascular endothelial cells were cultured in the graft under static culture conditions and compared to cultures obtained from dynamic continuous flow bioreactors. Immunofluorescent analysis showed that endothelial cells form a continuous luminal layer and functional characteristics were confirmed by uptake of acetylated low-density-lipoprotein. Incorporation of vancomycin and gentamicin to the medial graft layer allowed antimicrobial inhibition without exhibiting an adverse impact on cell viability. Most striking a physiological hemocompatibility was achieved for the multilayered grafts.},
  language  = {en}
}