Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

Expert Opinion on Drug Discovery

Volumn 12, Issue 7, 2017, Pages 711-731

  Mydock McGrane, Laurel K ^a   Hannan, Thomas J ^a   Janetka, James W ^b  

^a Fimbrion Therapeutics Inc   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AIEC; bacterial adhesin; Crohn s disease; FimH; lectin; mannoside; pili; structure based drug design (SBDD); UPEC; UTI

Indexed keywords

ADHESIN; AGLYCONE; DISACCHARIDE; GLYCOSIDE; INDOLE DERIVATIVE; MANNOSE; MANNOSE BINDING LECTIN; MANNOSIDE; NEW DRUG; PROTEIN; PROTEIN FIMH; TYPE 1 PILI; TYROSINE; UNCLASSIFIED DRUG; ANTIINFECTIVE AGENT; FIMBRIA PROTEIN; FIMH PROTEIN, E COLI;

BINDING AFFINITY; CROHN DISEASE; CRYSTAL STRUCTURE; DRUG EFFICACY; DRUG HALF LIFE; HOST CELL; HUMAN; HYDROGEN BOND; METABOLIC STABILITY; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN FUNCTION; PROTEIN STRUCTURE; RENAL CLEARANCE; REVIEW; URINARY TRACT INFECTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOAVAILABILITY; DISEASE MODEL; DRUG DESIGN; ESCHERICHIA COLI INFECTIONS; ISOLATION AND PURIFICATION; MICROBIOLOGY; MOUSE; STRUCTURE ACTIVITY RELATION; URINARY TRACT INFECTIONS; UROPATHOGENIC ESCHERICHIA COLI;

ADHESINS, ESCHERICHIA COLI; ANIMALS; ANTI-BACTERIAL AGENTS; BIOLOGICAL AVAILABILITY; CROHN DISEASE; DISEASE MODELS, ANIMAL; DRUG DESIGN; ESCHERICHIA COLI INFECTIONS; FIMBRIAE PROTEINS; HUMANS; MANNOSIDES; MICE; STRUCTURE-ACTIVITY RELATIONSHIP; URINARY TRACT INFECTIONS; UROPATHOGENIC ESCHERICHIA COLI;

EID: 85020702920     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1080/17460441.2017.1331216     Document Type: Review

References (123)

1. Ronald AR, Nicolle LE, Stamm E, et al. Urinary tract infection in adults:research priorities and strategies. Int J Antimicrob Agents. 2001;17(4):343–348.
2. Foxman B., Recurring urinary tract infection:incidence and risk factors. Am J Public Health. 1990;80(3):331–333.
3. Foxman B. Urinary tract infection syndromes:occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. 2014;28(1):1–13.
4. Griebling TL. Urinary tract infection in women. In:Litwin MS, Saigal CS, Editors. Urologic diseases in America. Washington (DC):In US Government Printing Office; 2007. p. 587–620.
5. Sanchez GV, Master RN, Bordon J. Trimethoprim-sulfamethoxazole may no longer be acceptable for the treatment of acute uncomplicated cystitis in the United States. Clin Infect Dis. 2011;53(3):316–317.
6. Karlowsky JA, Hoban DJ, Decorby MR, et al. Fluoroquinolone-resistant urinary isolates of Escherichia coli from outpatients are frequently multidrug resistant:results from the North American Urinary Tract Infection Collaborative Alliance-Quinolone Resistance study. Antimicrob Agents Chemother. 2006;50(6):2251–2254.
7. Zhanel G, Hisanaga T, Laing N, et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates:final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Ag. 2006;27(6):468–475.
8. Schaeffer A. The expanding role of fluoroquinolones. Disease-a-month. 2003;49(2):129–147.
9. Dielubanza E, Schaeffer A. Urinary tract infections in women. Med Clin Am. 2011;95(1):27–41.
10. Cole ST. Who will develop new antibacterial agents? Philos Trans Royal Soc B:Biol Sci. 2014;369(1645):20130430.
11. Nathan C. Fresh approaches to anti-infective therapies. Sci Transl Med. 2012;4(140):140sr2.
12. Lee YM, Almqvist F, Hultgren SJ. Targeting virulence for antimicrobial chemotherapy. Curr Opin Pharmacol. 2003;3(5):513–519.
13. Rasko DA, Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov. 2010;9(2):117–128.
14. Garland M, Loscher S, Bogyo M. Chemical strategies to target bacterial virulence. Chem Rev. 2017;117(5):4422–4461.• Excellent recent review on anti-virulence approaches, other than FimH and adhesins.
15. Cozens D, Read RC. Anti-adhesion methods as novel therapeutics for bacterial infections. Expert Rev Anti Infect Ther. 2012;10(12):1457–1468.
16. McGann P, Snesrud E, Maybank R, et al. Escherichia coli harboring mcr-1 and blaCTX-M on a novel IncF plasmid:first report of mcr-1 in the United States. Antimicrob Agents Chemother. 2016;60(7):4420–4421.• First reported case of a patient bearing a pan-antibiotic-resistant UPEC UTI in the US.
17. Mediavilla JR, Patrawalla A, Chen L, et al. Colistin- and carbapenem-resistant Escherichia coli harboring mcr-1 and blaNDM-5, causing a complicated urinary tract infection in a patient from the United States. mBio. 2016;7(4):e01191–01116.
18. Snyder J, Lloyd A, Lockatell C, et al. Role of phase variation of type 1 fimbriae in a uropathogenic Escherichia coli cystitis isolate during urinary tract infection. Infect Immun. 2006;74(2):1387–1393.
19. Wu XR, Sun TT, Medina JJ. In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib:relation to urinary tract infections. Proc Natl Acad Sci USA. 1996;93(18):9630–9635.
20. Anderson GG, Palermo JJ, Schilling JD, et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science. 2003;301(5629):105–107.
21. Zhou G, Mo WJ, Sebbel P, et al. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli:evidence from in vitro FimH binding. J Cell Sci. 2001;114(Pt 22):4095–4103.
22. Dorta DA, Sivignon A, Chalopin T, et al. The antiadhesive strategy in Crohn’s disease:orally active mannosides to decolonize pathogenic Escherichia coli from the gut. Chembiochem. 2016;17(10):936–952.•• Demonstration of in vivo efficacy of a FimH antagonist in Crohn’s disease.
23. Duguid JP, Gillies RR. Fimbriæ and adhesive properties in dysentery bacilli. J Path Bact. 1957;74(2):397–411.• The first mention of mannose as a possible inhibitor of E. coli attachment.
24. Ofek I, Mirelman D, Sharon N. Adherence of Escherichia coli to human mucosal cells mediated by mannose receptors. Nature. 1977;265:623–625.
25. Aronson M, Medalia O, Schori L, et al. Prevention of colonization of the urinary tract of mice with Escherichia coli by blocking of bacterial adherence with methyl a-D-mannopyranoside. J Infect Dis. 1979;139:329–332.• First paper describing mannosides as strategy to block type 1 pili in UTI.
26. Firon N, Ofek I, Sharon N. Interaction of mannose-containing oligosaccharides with the fimbrial lectin of Escherichia coli. Biochem Biophys Res Commun. 1982;105(4):1426–1432.
27. Firon N, Ofek I, Sharon N. Carbohydrate specificity of the surface lectins of Escherichia coli, Klebsiella pneumoniae, and Salmonella typhimurium. Carb Res. 1983;120:235–249.
28. Firon N, Ashkenazi S, Mirelman D, et al. Aromatic alpha-glycosides of mannose are powerful inhibitors of the adherence of type 1 fimbriated Escherichia coli to yeast and intestinal epithelial cells. Infect Immun. 1987;55(2):472–476.• Discovery of monomeric aryl mannosides as FimH ligands.
29. Andrade JRC. Role of fimbrial adhesiveness in experimental guinea pig kerato conjunctivitis by shigella flexneri. Rev Microbiol. 1980;11(4):117–125.
30. Neeser J, Koellreutter B, Wuersch P. Oligomannoside-type glycopeptides inhibiting adhesion of Escherichia coli strains mediated by type 1 pili:preparation of potent inhibitors from plant glycoproteins. Infect Immun. 1986;52(4):428–436.
31. Mydock-McGrane LK, Cusumano ZT, Janetka JW. Mannose-derived FimH antagonists:a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn’s disease. Expert Opin Ther Pat. 2016;26(2):175–197.•• Recent patent literature review on FimH antagonists.
32. Klein T, Abgottspon D, Wittwer M, et al. FimH antagonists for the oral treatment of urinary tract infections:from design and synthesis to in vitro and in vivo evaluation. J Med Chem. 2010;53(24):8627–8641.
33. Rabbani S, Jiang X, Schwardt O, et al. Expression of the carbohydrate recognition domain of FimH and development of a competitive binding assay. Anal Biochem. 2010;407(2):188–195.
34. Lindhorst TK, Kotter S, Krallmann-Wenzel U, et al. Trivalent alpha-D-mannoside clusters as inhibitors of type-1 fimbriae-mediated adhesion of Escherichia coli:structural variation and biotinylation. J Chem Soc Perkin Trans I. 2001;8:823–831.
35. Brument S, Sivignon A, Dumych TI, et al. Thiazolylaminomannosides as potent antiadhesives of type 1 piliated Escherichia coli isolated from Crohn’s disease patients. J Med Chem. 2013;56(13):5395–5406.• Identification of N-mannoside ‘TazMan’ FimH ligands in Crohn’s disease, AIEC bacteria.
36. Chalopin T, Dorta DA, Sivignon A, et al. Second generation of thiazolylmannosides, FimH antagonists for E. coli-induced Crohn’s disease. Org Biomol Chem. 2016;14(16):3913–3925.
37. Han Z, Pinkner JS, Ford B, et al. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem. 2010;53(12):4779–4792.•• Discovery of biphenyl and biaryl mannosides, X-ray structure and key SAR.
38. Kleeb S, Pang L, Mayer K, et al. FimH antagonists:bioisosteres to improve the in vitro and in vivo PK/PD profile. J Med Chem. 2015;58(5):2221–2239.
39. Bouckaert J, Berglund J, Schembri M, et al. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol Microbiol. 2005;55(2):441–455.•• X-ray crystal structure of D-Mannose and butylmannoside bound to FimH enabling rational structure-based design of mannosides.
40. Pang L, Kleeb S, Lemme K, et al. FimH antagonists:structure-activity and structure-property relationships for biphenyl alpha-D-mannopyranosides. ChemMedChem. 2012;7(8):1404–1422.
41. Han Z, Pinkner JS, Ford B, et al. Lead optimization studies on FimH antagonists:discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. J Med Chem. 2012;55(8):3945–3959.
42. Kranz JK, Schalk-Hihi C. Protein thermal shifts to identify low molecular weight fragments. Methods Enzymol. 2011;493:277–298.
43. Niesen F, Berglund H, Vedadi M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc. 2007;2(9):2212–2221.
44. Hultgren S, Schwan W, Schaeffer A, et al. Regulation of production of type 1 pili among urinary tract isolates of Escherichia coli. Infect Immun. 1986;54(3):613–620.
45. Mydock-McGrane L, Cusumano Z, Han Z, et al. Antivirulence C-mannosides as antibiotic-sparing, oral therapeutics for urinary tract infections. J Med Chem. 2016;59:9390–9408.•• Report of C-mannoside FimH antagonists with significantly enhanced metabolic stability.
46. Jarvis C, Han Z, Kalas V, et al. Antivirulence isoquinolone mannosides:optimization of the biaryl aglycone for FimH lectin binding affinity and efficacy in the treatment of chronic UTI. ChemMedChem. 2016;11(4):367–373.
47. Abgottspon D, Rölli G, Hosch L, et al. Development of an aggregation assay to screen FimH antagonists. J Microbiol Methods. 2010;82:249–255.
48. O’Toole G, Kolter R. Initiation of biofilm formation in Pseudomonas fluorescens WCS365 proceeds via multiple, convergent signalling pathways:a genetic analysis. Mol Microbiol. 1998;28(3):449–461.
49. Cegelski L, Pinkner J, Hammer N, et al. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nat Chem Biol. 2009;5(12):913–919.
50. Pinkner JS, Remaut H, Buelens F, et al. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci USA. 2006;103(47):17897–17902.
51. Blango MG, Mulvey MA. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob Agents Chemother. 2010;54(5):1855–1863.
52. Scharenberg M, Abgottspon D, Cicek E, et al. A flow cytometry-based assay for screening FimH antagonists. Assay Drug Dev Technol. 2011;9(5):455–464.
53. Kalas V, Pinkner JS, Hannan TJ, et al. Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions. Sci Adv. 2017;3(2):e1601944.• Key paper describing FimH conformational variability in UPEC.
54. Eris D, Preston RC, Scharenberg M, et al. The conformational variability of FimH:which conformation represents the therapeutic target? Chembiochem. 2016;17(11):1012–1020.• Key paper describing differential binding of mannosides to different bacterial strains.
55. Sauer MM, Jakob RP, Eras J, et al. Catch-bond mechanism of the bacterial adhesin FimH. Nat Commun. 2016;7:10738.
56. Hannan TJ, Mysorekar IU, Hung CS, et al. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. Plos Pathog. 2010;6(8):e1001042.
57. Hannan TJ, Totsika M, Mansfield KJ, et al. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev. 2012;36(3):616–648.
58. Hung CS, Dodson KW, Hultgren SJ. A murine model of urinary tract infection. Nat Protoc. 2009;4(8):1230–1243.
59. Justice SS, Hung C, Theriot JA, et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci USA. 2004;101(5):1333–1338.
60. Schwartz DJ, Conover MS, Hannan TJ, et al. Uropathogenic Escherichia coli superinfection enhances the severity of mouse bladder infection. Plos Pathog. 2015;11(1):e1004599.
61. Wright KJ, Seed PC, Hultgren SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol. 2007;9(9):2230–2241.
62. Cusumano CK, Pinkner JS, Han Z, et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med. 2011;3(109):109ra15.•• Demonstration of oral efficacy of a mannoside FimH antagonist in acute and chronic animal models of UTI. First reported in vivo efficacy of any anti-virulence therapeutic in a bacterial infection.
63. Totsika M, Kostakioti M, Hannan TJ, et al. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J Infect Dis. 2013;208(6):921–928.• FimH mannosides are effective at treating EBSL and MDR forms of UPEC.
64. Keane WF, Freedman LR. Pyelonephritis in normal mice produced by inoculation of E. coli into bladder lumen during water diuresis. Yale J Biol Med. 1967;40(3):231–237.
65. Murawski IJ, Maina RW, Malo D, et al. The C3H/HeJ inbred mouse is a model of vesico-ureteric reflux with a susceptibility locus on chromosome 12. Kidney Int. 2010;78(3):269–278.
66. Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, et al. Intercontinental emergence of Escherichia coli clone O25:H4-ST131producing CTX-M-15. J Antimicrob Chemother. 2008;61(2):273–281.
67. Barnich N, Carvalho FA, Glasser AL, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007;117(6):1566–1574.
68. Carvalho FA, Barnich N, Sivignon A, et al. Crohn’s disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM. J Exp Med. 2009;206(10):2179–2189.
69. Sivignon A, Yan X, Dorta DA, et al. Development of heptylmannoside-based glycoconjugate antiadhesive compounds against adherent-invasive Escherichia coli Bacteria associated with Crohn’s disease. mBio. 2015;6(6):e01298–e01215.
70. Kuehn MJ, Heuser J, Normark S, et al. P pili in uropathogenic E. coli are composite fibers with distinct fibrillar adhesive tips. Nature. 1992;356:252–255.
71. Sauer FG, Pinkner JS, Waksman G, et al. Chaperone priming of pilus subunits facilitates a topological transition that drives fiber formation. Cell. 2002;111:543–551.
72. Geibel S, Procko E, Hultgren SJ, et al. Structural and energetic basis of folded protein transport by the FimD usher. Nature. 2013;496:243–246.• Paper describing the up-to-date mechanism of pilus assembly in type 1 pili.
73. Remaut H, Rose RJ, Hannan TJ, et al. Donor-strand exchange in chaperone-assisted pilus assembly proceeds through a concerted beta strand displacement mechanism. Mol Cell. 2006;22(6):831–842.
74. Sauer FG, Fütterer K, Pinkner JS, et al. Structural basis of chaperone function and pilus biogenesis. Science. 1999;285(5430):1058–1061.
75. Hung CS, Bouckaert J, Hung D, et al. Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection. Mol Microbiol. 2002;44(4):903–915.
76. Wellens A, Garofalo C, Nguyen H, et al. Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH oligomannose-3 complex. Plos One. 2008;3(4):e2040.
77. Chen SL, Hung CS, Pinkner JS, et al. Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding. Proc Natl Acad Sci USA. 2009;106(52):22439–22444.
78. Knight SD, Bouckaert J. Structure, function, and assembly of type 1 fimbriae. Top Curr Chem. 2009;288:67–107.
79. Bouckaert J, Mackenzie J, de Paz JL, et al. The affinity of the FimH fimbrial adhesin is receptor-driven and quasi-independent of Escherichia coli pathotypes. Mol Microbiol. 2006;61(6):1556–1568.
80. Wellens A, Lahmann M, Touaibia M, et al. The tyrosine gate as a potential entropic lever in the receptor-binding site of the bacterial adhesin FimH. Biochemistry. 2012;51:4790–4799.
81. Roos G, Wellens A, Touaibia M, et al. Validation of reactivity descriptors to assess the aromatic stacking within the tyrosine gate of FimH. Med Chem Lett. 2013;4:1085–1090.
82. Rabbani S, Krammer EM, Roos G, et al. Mutation of Tyr137 of the universal Escherichia coli fimbrial adhesin FimH relaxes the tyrosine gate prior to mannose binding. IUCrJ. 2017;4(1):7–23.
83. Sperling O, Fuchs A, Lindhorst TK. Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH:design, synthesis and binding properties of mannoside ligands. Org Biomol Chem. 2006;4(21):3913–3922.
84. Jiang X, Abgottspon D, Kleeb S, et al. Antiadhesion therapy for urinary tract infections–a balanced PK/PD profile proved to be key for success. J Med Chem. 2012;55(10):4700–4713.• Paper systematically profiling PK and PD of FimH antagonists for UTI.
85. Sharon N. Bacterial lectins, cell-cell recognition and infectious disease. FEBS Lett. 1987;217(2):145–157.
86. Fiege B, Rabbani S, Preston RC, et al. The tyrosine gate of the bacterial lectin FimH:a conformational analysis by NMR spectroscopy and X-ray crystallography. Chembiochem. 2015;16(8):1235–1246.
87. Grabosch C, Hartmann M, Schmidt-Lassen J, et al. Squaric acid monoamide mannosides as ligands for the bacterial lectin FimH:covalent inhibition or not? Chembiochem. 2011;12:1066–1074.
88. Schwardt O, Rabbani S, Hartmann M, et al. Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists. Bioorg Med Chem Lett. 2011;19(21):6454–6473.
89. Car Z, Hrenar T, Petrović Peroković VP, et al. Mannosylated N-aryl substituted 3-hydroxypyridine-4-ones:synthesis, hemagglutination inhibitory properties, and molecular modeling. Chem Biol Drug Des. 2014;84:393–401.
90. Tomašić T, Rabbani S, Gobec M, et al. Branched:a-D-mannopyranosides:a new class of potent FimH antagonists. Med Chem Commun. 2014;5(8):1247–1253.
91. Chandrasekaran V, Kolbe K, Beiroth F, et al. Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH. Beilstein J Org Chem. 2013;9:223–233.
92. Hartmann M, Papavlassopoulos H, Chandrasekaran V, et al. Inhibition of bacterial adhesion to live human cells:activity and cytotoxicity of synthetic mannosides. FEBS Lett. 2012;586:1459–1465.• Paper describing lack of toxicity found for several mannosides against mammalian cells.
93. Rodriguez VB, Kidd BA, Interlandi G, et al. Allosteric coupling in the bacterial adhesive protein FimH. J Biol Chem. 2013;288(33):24128–24139.
94. Yakovenko O, Tchesnokova V, Sokurenko EV, et al. Inactive conformation enhances binding function in physiological conditions. Proc Natl Acad Sci USA. 2015;112(32):9884–9889.
95. Feenstra T, Thogersen MS, Wieser E, et al. Adhesion of Escherichia coli under flow conditions reveals potential novel effects of FimH mutations. Eur J Clin Microbiol Infect Dis. 2017;36(3):467–478.
96. Szunerits S, Zagorodko O, Cogez V, et al. Differentiation of Crohn’s disease-associated isolates from other pathogenic Escherichia coli by fimbrial adhesion under shear force. Biology (Basel). 2016;5(2):14.
97. Mockl L, Fessele C, Despras G, et al. En route from artificial to natural:evaluation of inhibitors of mannose-specific adhesion of E. coli under flow. Biochim Biophys Acta. 2016;1860(9):2031–2036.
98. Di L, Kerns EH. Profiling drug-like properties in discovery research. Curr Opin Chem Biol. 2003;7(3):402–408.
99. Ito S, Ando H, Ose A, et al. Relationship between the urinary excretion mechanisms of drugs and their physicochemical properties. J Pharm Sci. 2013;102(9):3294–3301.
100. de Ruyck J, Lensink MF, Bouckaert J. Structures of C-mannosylated anti-adhesives bound to the type 1 fimbrial FimH adhesin. IUCrJ. 2016;3(Pt 3):163–167.• First reported X-ray structural information on simple C-linked biphenyl mannosides.
101. Bennani YL, Cadilhac C, Das SK, et al. Mannose derivatives for treating bacterial infections.WO/2013/134415. 2013.
102. Bennani YL, Liu B. Mannose derivatives for treating bacterial infections.WO/2014/055474. 2014.
103. Dietrich E, Poisson C, Gallant M, et al. Mannoside derivatives for treating bacterial infections.WO2014/165107A2. 2014.• Vertex patent covering mannose dimers which could include clinical candidate EB8018.
104. Schönemann W, Kleeb S, Dätwyler P, et al. Prodruggability of carbohydrates–oral FimH antagonists. Can J Chem. 2016;94(11):909–919.• Prodrug approach to mannosides.
105. Kleeb S, Jiang X, Frei P, et al. FimH antagonists:phosphate prodrugs improve oral bioavailability. J Med Chem. 2016;59(7):3163–3182.• Phosphate prodrug approach to mannosides.
106. Lee RT, Lee YC. Affinity enhancement by multivalent lectin-carbohydrate interaction. Glycoconj J. 2000;17:543–551.
107. Nagahori N, Lee RT, Nishimura S-I, et al. Inhibition of adhesion of type 1 fimbriated Escherichia coli to highly mannosylated ligands. Chembiochem. 2002;3:836–844.
108. Papadopoulos A, Shiao TC, Roy R. Diazo transfer and click chemistry in the solid phase syntheses of lysine-based glycodendrimers as antagonists against Escherichia coli FimH. Mol Pharm. 2012;9:394–403.
109. Chalopin T, Brissonnet Y, Sivignon A, et al. Inhibition profiles of mono- and polyvalent FimH antagonists against 10 different Escherichia coli strains. Org Biomol Chem. 2015;13:11369–11375.
110. Yan X, Sivignon A, Yamakawa N, et al. Glycopolymers as antiadhesives of E. coli strains inducing inflammatory bowel diseases. Biomacromolecules. 2015;16:1827–1836.
111. Bouckaert J, Li Z, Xavier C, et al. Heptyl alpha-D-mannosides grafted on a beta-cyclodextrin core to interfere with Escherichia coli adhesion:an in vivo multivalent effect. Chemistry. 2013;19(24):7847–7855.
112. Gouin SG, Wellens A, Bouckaert J, et al. Synthetic multimeric heptyl mannosides as potent antiadhesives of uropathogenic Escherichia coli. ChemMedChem. 2009;4(5):749–755.
113. Yan X, Sivignon A, Barnich N, et al. A library of heptyl mannose-functionalized copolymers with distinct compositions, microstructures and neighboring non-sugar motifs as potent antiadhesives of type 1 piliated E. Coli Polym Chem. 2016;7:2674–2683.
114. Almant M, Moreau V, Kovensky J, et al. Clustering of Escherichia coli type-1 fimbrial adhesins by using multimeric heptyl a-D-mannoside probes with a carbohydrate core. Chem Eur J. 2011;17:10029–10038.
115. Lindhorst TK, Kieburg C, Krallmann-Wenzel U. Inhibition of the type 1 fimbriae-mediated adhesion of Escherichia coli to erythrocytes by multiantennary alpha-mannosyl clusters:the effect of multivalency. Glycoconj J. 1998;15(6):605–613.
116. Kötter S, Krallmann-Wenzel U, Ehlers S, et al. Multivalent ligands for the mannose-specific lectin on type 1 fimbriae of Escherichia coli:syntheses and testing of trivalent a-D-mannoside clusters. J Chem Soc Perkin Trans I. 1998;14:2193–2200.
117. Schierholt A, Hartmann M, Lindhorst TK. Bi- and trivalent glycopeptide mannopyranosides as inhibitors of type 1 fimbriae-mediated bacterial adhesion:variation of valency, aglycon and scaffolding. Carb Res. 2011;346:1519–1526.
118. Barras A, Martin FA, Bande O, et al. Glycan-functionalized diamond nanoparticles as potent E. coli anti-adhesives. Nanoscale. 2013;5:2307–2316.
119. Durka M, Buffet K, Iehl J, et al. The functional valency of dodecamannosylated fullerenes with Escherichia coli FimH–towards novel bacterial antiadhesivesw. Chem Commun. 2011;47:1321–1323.
120. Touaibia M, Wellens A, Shiao TC, et al. Mannosylated G(0) dendrimers with nanomolar affinities to Escherichia coli FimH. ChemMedChem. 2007;2(8):1190–1201.
121. Sattin S, Bernardi A. Glycoconjugates and glycomimetics as microbial anti-adhesives. Trends Biotechnol. 2016;34(6):483–495.• Nice review of multivalent ligands of FimH and other bacterial lectins.
122. Cecioni S, Imberty A, Vidal S. Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. Chem Rev. 2015;115(1):525–561.• Excellent review on the glycodendrimer inhibitors of lectins in drug discovery.
123. Ramtohul YK, Das SK, Cadilhac C, et al. Mannose derivatives for treating bacterial infections.WO/2014/100158. 2014.• Vertex patent which might cover clinical candidate EB8018.