TY - JOUR
T1 - Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections
AU - Mydock-McGrane, Laurel
AU - Cusumano, Zachary
AU - Han, Zhenfu
AU - Binkley, Jana
AU - Kostakioti, Maria
AU - Hannan, Thomas
AU - Pinkner, Jerome S.
AU - Klein, Roger
AU - Kalas, Vasilios
AU - Crowley, Jan
AU - Rath, Nigam P.
AU - Hultgren, Scott J.
AU - Janetka, James W.
N1 - Funding Information:
This work was funded in part by the NIH grants 1RC1DK086378 (Washington University) from NIDDK, and 5R43AI106112-02 (Fimbrion Therapeutics, Inc.) from NIAID. Support for the Biomedical Mass Spectrometry Resource to do the mouse urine PK bioanalytical studies is provided by the NIH/NIGMS grant no. P41GM103422
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/10/27
Y1 - 2016/10/27
N2 - Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.
AB - Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.
UR - http://www.scopus.com/inward/record.url?scp=84994045694&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00948
DO - 10.1021/acs.jmedchem.6b00948
M3 - Article
C2 - 27689912
AN - SCOPUS:84994045694
SN - 0022-2623
VL - 59
SP - 9390
EP - 9408
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -