Biology Reference
In-Depth Information
with PapD ( Pinkner et al., 2006 ; Chorell et al., 2010 ). The pilicides were shown
to bind with a conserved, hydrophobic, solvent-exposed patch at the N-terminal
side of the chaperone ( Figure 12.6 C,D), the presumed usher-binding site, thus
explaining the structural basis of their mechanism of action.
Translated to clinical practice, mannosides, pilicides, and vaccine options
can be cost-effective ways to prevent and treat UTIs and other infections that
require CU pili, while reducing antibiotic resistance. Using specific antiviru-
lence therapeutics should have minimal impact on the composition of host
microbiota, reducing the risk of opportunistic or recurrent infections.
CONCLUSION
Gram-negative bacteria use the CU pathway to assemble virulent surface
appendages called pili. Structural biology combined with genetic and bio-
chemical approaches has elucidated crucial protein-protein interactions
made by the dedicated chaperone and ushers to facilitate the ordered assem-
bly of pilins into the final pilus structure on the extracellular surface, as well
as protein-carbohydrate interactions required for virulence. This work has
generated new insights into protein folding and revealed novel mechanisms
of macromolecular assembly. Chaperones stabilize the fold of each subunit
in a chaperone-subunit complex, in which the subunit is held in a high-
energy conformation primed to participate in pilus assembly at the usher.
Ushers catalyze pilus assembly through interactions with each chaperone-
subunit complex, coordinating the release of the chaperone and interactions
of subunits with each other as they fold into their final condensed struc-
tures and translocate through the outermembrane usher pore. These multi-
disciplinary approaches have revealed snapshots of a sophisticated protein
assembly machinery, elucidated the virulence mechanisms of bacteria, and
led to development of therapeutics that suppress infection in animal models.
Ultimately, these efforts will lead to a better understanding of CU pilus-
mediated infectious disease, giving rise to potent therapeutics that target
acute, chronic, and recurrent infections for prevention and treatment of
human disease.
REFERENCES
Anderson, G.G., Palermo, J.J., Schilling, J.D., Roth, R., Heuser, J., Hultgren, S.J., 2003. Intracel-
lular bacterial bioilm-like pods in urinary tract infections. Science 301, 105-107 .
Baga, M., Norgren, M., Normark, S., 1987. Biogenesis of E. coli Pap pili: papH, a minor pilin sub-
unit involved in cell anchoring and length modulation. Cell 49, 241-251 .
Bahrani-Mougeot, F.K., Buckles, E.L., Lockatell, C.V., et al., 2002. Type 1 imbriae and extracel-
lular polysaccharides are preeminent uropathogenic Escherichia coli virulence determinants in
the murine urinary tract. Mol. Microbiol. 45, 1079-1093 .
Bann, J.G., Pinkner, J.S., Frieden, C., Hultgren, S.J., 2004. Catalysis of protein folding by chaper-
ones in pathogenic bacteria. Proc. Natl. Acad. Sci. USA 101, 17389-17393 .
Search WWH ::




Custom Search