Adhesive pili of the chaperone-usher family - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 367

FIGURE 12.6 CU pili as antibacterial targets. (A) Crystal structure of a mannoside (cyan) in
complex with the FimH lectin domain (magenta) [PDB code: 3MCY]. (B) Mannoside prevents
IBC formation and can treat established infections ( Cusumano et al., 2011 ). Confocal microscopy
of mice bladders depicts an intracellular bacterial community (IBC, green) in the left panel and
prevention of IBC formation with mannoside treatment in the right panel (white arrows indicate
luminal bacteria). (C) Crystal structure of a pilicide (cyan) bound to PapD (green). The pilicide
binds to the F1, C1, and D1” strands, a region thought to be the usher-targeting site of the protein,
where many of the Set B residues coincide [PDB code: 2J7L]. (D) Pilicide inhibits type 1 pilus and
P pilus assembly. Atomic force microscopy images show a piliated, untreated bacterium (left panel)
and a naked, pilicide-treated bacterium (right panel), indicating that pilicides suppress pilus biogen-
esis. (B) and (D) are reproduced, with permission, from Cusumano et al. (2011) and Waksman and
Hultgren (2009) .
cells. These mannosides not only block adhesion but also counteract internal-
ization and in vitro/in vivo biofilm formation on biotic and abiotic surfaces
( Cusumano et al., 2011 ; Guiton et al., 2012 ) ( Figure 12.6 A,B). Furthermore,
mannosides potentiate the efficacy of existing antibiotics in a murine model
of UTI and have great oral bioavailability, increasing hopes that they can be
used in drug development ( Cusumano et al., 2011 ). Similar to FimH, PapG was
also a target for antivirulence therapeutics design such that p-Methoxy-phenyl
derivatives of galabiose inhibit PapG with low micromolar IC 50 (half-maximal
inhibitory concentration) values ( Hultgren et al., 1989 ; George et al., 2001 ; Lin
et al., 2012 ; Ohlsson et al., 2002 ).
In addition to targeting the receptor-binding site of the mature pilus, com-
pounds that directly interfere with pilus biogenesis have also been developed.
These rationally designed bicyclic 2-pyridone compounds, termed pilicides,
inhibit UPEC hemagglutination of erythrocytes and biofilm formation by inhib-
iting both P and type 1 pilus biogenesis ( Pinkner et al., 2006 ). X-ray crystal-
lography and biochemical studies revealed an interaction of these compounds