Compounds against acute and disseminating Neisseria infection
Department of Microbiology
Neisseria gonorrhoeae is an obligate human pathogen. This gram negative bacterium is the causing agent of gonorrhea, one of the most common sexually transmitted diseases. In a certain number of cases bacteria will end up in blood stream, causing disseminating neisserial infection, coupled with complications such as endo- und perikarditis, arthritis, sepsis, pneumonia und meningitis. The important prerequisite for neisserial infection is adherence to epithelial cells, which is mediated by Pili, Opa proteins and PorBIA porins. PorBIA interacts with Gp96 and SREC-I receptor on the cell surface. This interaction supports bacterial invasion and plays an important role in disseminating infection. Another significant player in persistent and disseminated goncoccal infection is the Macrophage Infection Potentiator (MIP), which enables the survival of gonococci in macrophages. We therefore plan to optimize the known inhibitors of MIP and to identify new inhibitors of PorBIA/SREC-I interactions from already existing compound libraries. Our further goal is to solve the structure of SREC-I ectodomain. This will, together with the already obtained PorBIA structure, help us to make a model for the PorBIA/SREC-I binding, which in turn will serve to develop and optimize other compounds that can inhibit this interaction and eventually be used in therapy of recurrent and disseminating neisserial infections.
M. Faulstich, J. P. Bottcher, T. F. Meyer, M. Fraunholz, T. Rudel; Pilus phase variation switches gonococcal adherence to invasion by caveolin-1-dependent host cell signaling. PLoS Pathog 2013, 9, e1003373. doi:10.1371/journal.ppat.1003373
K. Zeth, V. Kozjak-Pavlovic, M. Faulstich, M. Fraunholz, R. Hurwitz, O. Kepp, T. Rudel; Structure and function of the PorB porin from disseminating Neisseria gonorrhoeae. Biochem J 2013, 449, 631-642. doi:10.1042/BJ20121025
C. Ott, M. Utech, M. Goetz, T. Rudel, V. Kozjak-Pavlovic; The requirements for the import of neisserial Omp85 into the outer membrane of human mitochondria. Biosci Rep 2013. doi:10.1042/BSR20130007
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C. Rechner, C. Kuhlewein, A. Muller, H. Schild, T. Rudel; Host glycoprotein Gp96 and scavenger receptor SREC interact with PorB of disseminating Neisseria gonorrhoeae in an epithelial invasion pathway. Cell Host Microbe. 2007, 2, 393-403.
T. Rudel, H.J. Boxberger, T.F. Meyer; Pilus biogenesis and epithelial cell adherence of Neisseria gonorrhoeae pilC double knock-out mutants. Mol. Microbiol. 1995a, 17, 1057-1071.
T. Rudel, I. Scheuerpflug, T.F. Meyer; Neisseria PilC protein identified as type-4 pilus tip-located adhesin. Nature 1995b, 373, 357-359.
T. Rudel, A. Schmid, R. Benz, H.A. Kolb, F. Lang, T.F. Meyer; Modulation of Neisseria porin (PorB) by cytosolic ATP/GTP of target cells: parallels between pathogen accommodation and mitochondrial endosymbiosis. Cell 1996, 85, 391-402.
I. Scheuerpflug, T. Rudel, R. Ryll, J. Pandit, T.F. Meyer; Roles of PilC and PilE proteins in pilus-mediated adherence of Neisseria gonorrhoeae and Neisseria meningitidis to human erythrocytes and endothelial and epithelial cells. Infect. Immun. 1999, 67, 834-843.
J.A. Wang, T.F. Meyer, T. Rudel; Cytoskeleton and motor proteins are required for the transcytosis of Neisseria gonorrhoeae through polarized epithelial cells. Int. J. Med. Microbiol. 2008, 298, 209-221.