| 1. |
- Chorell, Erik, 1980-, et al.
(författare)
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Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones : pilicides with increased antivirulence activity
- 2010
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Ingår i: Journal of Medicinal Chemistry. - Washington, USA : American Chemical Society. - 0022-2623 .- 1520-4804. ; 53:15, s. 5690-5695
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.
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| 2. |
- Subedi, Suresh, et al.
(författare)
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Expression, purification and X-ray crystallographic analysis of the Helicobacter pylori blood group antigen-binding adhesin BabA
- 2014
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Ingår i: Acta Crystallographica Section F. - 2053-230X. ; 70, s. 1631-1635
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori is a human pathogen that colonizes about 50% of the world's population, causing chronic gastritis, duodenal ulcers and even gastric cancer. A steady emergence of multiple antibiotic resistant strains poses an important public health threat and there is an urgent requirement for alternative therapeutics. The blood group antigen-binding adhesin BabA mediates the intimate attachment to the host mucosa and forms a major candidate for novel vaccine and drug development. Here, the recombinant expression and crystallization of a soluble BabA truncation (BabA(25-460)) corresponding to the predicted extracellular adhesin domain of the protein are reported. X-ray diffraction data for nanobody-stabilized BabA 25-460 were collected to 2.25 angstrom resolution from a crystal that belonged to space group P2(1), with unit-cell parameters a = 50.96, b = 131.41, c = 123.40 angstrom, alpha = 90.0, beta = 94.8, gamma = 90.0 degrees, and which was predicted to contain two BabA(25-460)-nanobody complexes per asymmetric unit.
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| 3. |
- Wellens, Adinda, et al.
(författare)
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The Tyrosine Gate as a Potential Entropic Lever in the Receptor-Binding Site of the Bacterial Adhesin FimH
- 2012
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:24, s. 4790-4799
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Tidskriftsartikel (refereegranskat)abstract
- Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl alpha-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH inhibitor interactions indicate that the binding of FimH to alpha-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of alpha-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of alpha-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (approximate to 2.65 angstrom) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for alpha-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl alpha-D-mannose.
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