6AOX

F9 pilus adhesin FmlH lectin domain from E. coli UTI89 co-crystallized with TF antigen

Summary for 6AOX

• Entry DOI: 10.2210/pdb6aox/pdb
• Related PRD ID: PRD_900084
• Descriptor: Fml fimbrial adhesin FmlD, beta-D-galactopyranose-(1-3)-2-acetamido-2-deoxy-alpha-D-galactopyranose (3 entities in total)
• Functional Keywords: fimbrial adhesin, lectin, bacterial adhesion, sugar binding protein
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 36606.87

Authors

Kalas, V.,Hultgren, S.J. (deposition date: 2017-08-16, release date: 2018-02-28, Last modification date: 2023-10-04)

Primary citation

Kalas, V.,Hibbing, M.E.,Maddirala, A.R.,Chugani, R.,Pinkner, J.S.,Mydock-McGrane, L.K.,Conover, M.S.,Janetka, J.W.,Hultgren, S.J.
Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection.
Proc.Natl.Acad.Sci.USA, 115:E2819-E2828, 2018

PubMed 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 (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 -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 -acetylgalactosaminosides that inhibit the F9 pilus adhesin FmlH. The lead compound, 29β-NAc, is a biphenyl -acetyl-β-galactosaminoside with a 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.

PubMed: 29507247
DOI: 10.1073/pnas.1720140115

Experimental method

X-RAY DIFFRACTION (2.1 Å)