ยท JS. Pinkner, H. Remaut, F. Buelens, E.
Miller, V. Akberg, N. Pemberton, M. Hedenstrom, A. Larsson, P. Seed, G. Waksman*,
SJ. Hultgren* & F. Almqvist*
New Class of Rationally Designed Small Compounds Inhibit Pilus Biogenesis in
Uropathogenic Bacteria
Proc. Natl. Acad. Sci. USA. 103(47):17897-902 (2006)
A chemical synthesis platform with broad
applications and flexibility was rationally designed to inhibit biogenesis of
adhesive pili assembled by the chaperone-usher pathway in Gram-negative
pathogens. The activity of a new family of bicyclic 2-pyridones, termed
pilicides, was evaluated in two different pilus biogenesis systems in
uropathogenic E. coli. Hemagglutination mediated by either
type 1 or P pili, adherence to bladder cells and biofilm formation mediated by
type 1 pili were all reduced by approximately 90% in laboratory and clinical E.
coli strains. The
structure of the pilicide bound to the P pilus chaperone, PapD, revealed that
the pilicide bound to the surface of the chaperone known to interact with the
usher, the outer-membrane assembly platform where pili are assembled. Point
mutations in the pilicide binding site dramatically reduced pilus formation but
did not block the ability of PapD to bind subunits and mediate their folding.
Surface plasmon resonance experiments confirmed that the pilicide interfered
with the binding of chaperone-subunit complexes to the usher. These newly
designed pilicides thus target key virulence factors in pathogenic bacteria and
represent a promising new proof of concept for developing drugs that function
by targeting virulence factors.