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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
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