TY - JOUR
T1 - Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections
AU - Maddirala, Amarendar Reddy
AU - Tamadonfar, Kevin
AU - Pinkner, Jerome S.
AU - Sanick, Denise
AU - Hultgren, Scott J.
AU - Janetka, James W.
N1 - Publisher Copyright:
© 2024 American Chemical Society
PY - 2024/3/14
Y1 - 2024/3/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85184816626&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c02128
DO - 10.1021/acs.jmedchem.3c02128
M3 - Article
C2 - 38308631
AN - SCOPUS:85184816626
SN - 0022-2623
VL - 67
SP - 3668
EP - 3678
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -