Version 3 2024-02-19, 13:07Version 3 2024-02-19, 13:07
Version 2 2024-02-14, 16:36Version 2 2024-02-14, 16:36
Version 1 2024-02-03, 14:35Version 1 2024-02-03, 14:35
journal contribution
posted on 2024-02-19, 13:07authored byAmarendar
Reddy Maddirala, Kevin Tamadonfar, Jerome S. Pinkner, Denise Sanick, Scott J. Hultgren, James W. Janetka
FmlH,
a bacterial adhesin of uropathogenic Escherichia
coli (UPEC), has been shown to provide a fitness advantage
in colonizing the bladder during chronic urinary tract infections
(UTIs). Previously reported ortho-biphenyl glycosides
based on βGal and βGalNAc have excellent binding affinity
to FmlH and potently block binding to its natural carbohydrate receptor,
but they lack oral bioavailability. In this paper, we outline studies
where we have optimized compounds for improved pharmacokinetics, leading
to the discovery of novel analogues with good oral bioavailability.
We synthesized galactosides with the anomeric O-linker replaced with
more stable S- and C-linked linkers. We also investigated modifications
to the GalNAc sugar and modifications to the biphenyl aglycone. We
identified GalNAc 69 with an IC50 of 0.19
μM against FmlH and 53% oral bioavailability in mice. We also
obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic
for UTIs.