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Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2819-E2828. doi: 10.1073/pnas.1720140115. Epub 2018 Mar 5.

Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection.

Author information

1
Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110.
2
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
3
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110.
4
Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110; janetkaj@wustl.edu hultgren@wustl.edu.

Abstract

Treatment of bacterial infections is becoming a serious clinical challenge due to the global dissemination of multidrug antibiotic resistance, necessitating the search for alternative treatments to disarm the virulence mechanisms underlying these infections. Uropathogenic Escherichia coli (UPEC) employs multiple chaperone-usher pathway pili tipped with adhesins with diverse receptor specificities to colonize various host tissues and habitats. For example, UPEC F9 pili specifically bind galactose or N-acetylgalactosamine epitopes on the kidney and inflamed bladder. Using X-ray structure-guided methods, virtual screening, and multiplex ELISA arrays, we rationally designed aryl galactosides and N-acetylgalactosaminosides that inhibit the F9 pilus adhesin FmlH. The lead compound, 29β-NAc, is a biphenyl N-acetyl-β-galactosaminoside with a Ki of ∼90 nM, representing a major advancement in potency relative to the characteristically weak nature of most carbohydrate-lectin interactions. 29β-NAc binds tightly to FmlH by engaging the residues Y46 through edge-to-face π-stacking with its A-phenyl ring, R142 in a salt-bridge interaction with its carboxylate group, and K132 through water-mediated hydrogen bonding with its N-acetyl group. Administration of 29β-NAc in a mouse urinary tract infection (UTI) model significantly reduced bladder and kidney bacterial burdens, and coadministration of 29β-NAc and mannoside 4Z269, which targets the type 1 pilus adhesin FimH, resulted in greater elimination of bacteria from the urinary tract than either compound alone. Moreover, FmlH specifically binds healthy human kidney tissue in a 29β-NAc-inhibitable manner, suggesting a key role for F9 pili in human kidney colonization. Thus, these glycoside antagonists of FmlH represent a rational antivirulence strategy for UPEC-mediated UTI treatment.

KEYWORDS:

antibiotic-sparing therapeutic; glycomimetics; host–pathogen interactions; structure-based drug design; urinary tract infection

PMID:
29507247
PMCID:
PMC5866590
DOI:
10.1073/pnas.1720140115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: J.W.J. and S.J.H. are inventors on US patent US8937167 B2, which covers the use of mannoside-based FimH ligand antagonists for the treatment of disease. J.W.J., M.E.H., and S.J.H. have ownership interests in Fimbrion Therapeutics and may benefit if the company is successful in marketing mannosides.

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