Discovery of Potent Inhibitors of PapG Adhesins from Uropathogenic Escherichia coli through Synthesis and Evaluation of Galabiose Derivatives

Structure–activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins

“…All compounds showed higher affinities for the adhesin than those observed for aliphatic galabiosides (i.e. the 2-(trimethylsilyl)ethyl galabioside 46 18 ). The positions of methoxy groups on the aromatic aglycons had some impact on the affinity.…”

“…The presence of amides at C1 of galabiose (collection I) turned out to be detrimental to binding. The benzamido derivatives (5-8, and 10) displayed K d of 1.0-2.3 mM, which is much worse than that of the known reference compound p-methoxyphenyl galabioside 45 18 (K d 140 lM 21 ). Virtually no interaction was seen with an aliphatic amide at C1 (9).…”

“…It has been shown that for the PapG class II adhesin the galabiose disaccharide is such a key structure 17 necessary for recognition and that galabioside derivatives substituted at C1 and C3 often display enhanced affinity for the PapG adhesins. 18 Furthermore, the crystal structure of the class II PapG adhesin in complex with the globotetraose tetrasaccharide has been solved 19 and it confirmed that the galabiose disaccharide unit is the most critical structural element for the formation of the complex. The complex structure revealed an extended surface composed of H1, H2 and H6 of Gala, H1, H3, H4, H5 and H6 of Galb, and H2 and H4 of Glc, that make hydrophobic contact primarily with the Trp107 sidechain.…”

Structure–activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins

“…All compounds showed higher affinities for the adhesin than those observed for aliphatic galabiosides (i.e. the 2-(trimethylsilyl)ethyl galabioside 46 18 ). The positions of methoxy groups on the aromatic aglycons had some impact on the affinity.…”

“…The presence of amides at C1 of galabiose (collection I) turned out to be detrimental to binding. The benzamido derivatives (5-8, and 10) displayed K d of 1.0-2.3 mM, which is much worse than that of the known reference compound p-methoxyphenyl galabioside 45 18 (K d 140 lM 21 ). Virtually no interaction was seen with an aliphatic amide at C1 (9).…”

“…It has been shown that for the PapG class II adhesin the galabiose disaccharide is such a key structure 17 necessary for recognition and that galabioside derivatives substituted at C1 and C3 often display enhanced affinity for the PapG adhesins. 18 Furthermore, the crystal structure of the class II PapG adhesin in complex with the globotetraose tetrasaccharide has been solved 19 and it confirmed that the galabiose disaccharide unit is the most critical structural element for the formation of the complex. The complex structure revealed an extended surface composed of H1, H2 and H6 of Gala, H1, H3, H4, H5 and H6 of Galb, and H2 and H4 of Glc, that make hydrophobic contact primarily with the Trp107 sidechain.…”

Development of intracellular bacterial communities of uropathogenicEscherichia colidepends on type 1 pili

“…These defects were associated with a severe attenuation of virulence. Thus, our observations emphasize the importance of previous studies in developing type 1 pili as a therapeutic target (Langermann et al ., 1997; 2000; Langermann and Ballou, 2001; Svensson et al ., 2001; Ohlsson et al ., 2002). Finally, this novel role may represent a paradigm for other pathogenic organisms such as Pseudomonas aeruginosa which produce pili and have been observed to form IBC‐like communities within tracheal epithelial cells (Oh et al ., 2005).…”

Intervention with bacterial adhesion by multivalent carbohydrates

“…4). [60][61][62] In both cases, the compounds showed a relative inhibitory potency of around 7 with respect to the reference galabiose compound bearing the 2trimethylsilylethyl group at its reducing end (9). For S. suis, similar schematic studies have been undertaken as were mentioned for P-fimbriated E. coli.…”

Structure–activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins

“…All compounds showed higher affinities for the adhesin than those observed for aliphatic galabiosides (i.e. the 2-(trimethylsilyl)ethyl galabioside 46 18 ). The positions of methoxy groups on the aromatic aglycons had some impact on the affinity.…”

“…The presence of amides at C1 of galabiose (collection I) turned out to be detrimental to binding. The benzamido derivatives (5-8, and 10) displayed K d of 1.0-2.3 mM, which is much worse than that of the known reference compound p-methoxyphenyl galabioside 45 18 (K d 140 lM 21 ). Virtually no interaction was seen with an aliphatic amide at C1 (9).…”

“…It has been shown that for the PapG class II adhesin the galabiose disaccharide is such a key structure 17 necessary for recognition and that galabioside derivatives substituted at C1 and C3 often display enhanced affinity for the PapG adhesins. 18 Furthermore, the crystal structure of the class II PapG adhesin in complex with the globotetraose tetrasaccharide has been solved 19 and it confirmed that the galabiose disaccharide unit is the most critical structural element for the formation of the complex. The complex structure revealed an extended surface composed of H1, H2 and H6 of Gala, H1, H3, H4, H5 and H6 of Galb, and H2 and H4 of Glc, that make hydrophobic contact primarily with the Trp107 sidechain.…”

Development of intracellular bacterial communities of uropathogenicEscherichia colidepends on type 1 pili

“…These defects were associated with a severe attenuation of virulence. Thus, our observations emphasize the importance of previous studies in developing type 1 pili as a therapeutic target (Langermann et al ., 1997; 2000; Langermann and Ballou, 2001; Svensson et al ., 2001; Ohlsson et al ., 2002). Finally, this novel role may represent a paradigm for other pathogenic organisms such as Pseudomonas aeruginosa which produce pili and have been observed to form IBC‐like communities within tracheal epithelial cells (Oh et al ., 2005).…”

Intervention with bacterial adhesion by multivalent carbohydrates

“…4). [60][61][62] In both cases, the compounds showed a relative inhibitory potency of around 7 with respect to the reference galabiose compound bearing the 2trimethylsilylethyl group at its reducing end (9). For S. suis, similar schematic studies have been undertaken as were mentioned for P-fimbriated E. coli.…”

Structure–activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins

“…All compounds showed higher affinities for the adhesin than those observed for aliphatic galabiosides (i.e. the 2-(trimethylsilyl)ethyl galabioside 46 18 ). The positions of methoxy groups on the aromatic aglycons had some impact on the affinity.…”

“…The presence of amides at C1 of galabiose (collection I) turned out to be detrimental to binding. The benzamido derivatives (5-8, and 10) displayed K d of 1.0-2.3 mM, which is much worse than that of the known reference compound p-methoxyphenyl galabioside 45 18 (K d 140 lM 21 ). Virtually no interaction was seen with an aliphatic amide at C1 (9).…”

“…It has been shown that for the PapG class II adhesin the galabiose disaccharide is such a key structure 17 necessary for recognition and that galabioside derivatives substituted at C1 and C3 often display enhanced affinity for the PapG adhesins. 18 Furthermore, the crystal structure of the class II PapG adhesin in complex with the globotetraose tetrasaccharide has been solved 19 and it confirmed that the galabiose disaccharide unit is the most critical structural element for the formation of the complex. The complex structure revealed an extended surface composed of H1, H2 and H6 of Gala, H1, H3, H4, H5 and H6 of Galb, and H2 and H4 of Glc, that make hydrophobic contact primarily with the Trp107 sidechain.…”

Development of intracellular bacterial communities of uropathogenicEscherichia colidepends on type 1 pili

“…These defects were associated with a severe attenuation of virulence. Thus, our observations emphasize the importance of previous studies in developing type 1 pili as a therapeutic target (Langermann et al ., 1997; 2000; Langermann and Ballou, 2001; Svensson et al ., 2001; Ohlsson et al ., 2002). Finally, this novel role may represent a paradigm for other pathogenic organisms such as Pseudomonas aeruginosa which produce pili and have been observed to form IBC‐like communities within tracheal epithelial cells (Oh et al ., 2005).…”

Intervention with bacterial adhesion by multivalent carbohydrates

“…4). [60][61][62] In both cases, the compounds showed a relative inhibitory potency of around 7 with respect to the reference galabiose compound bearing the 2trimethylsilylethyl group at its reducing end (9). For S. suis, similar schematic studies have been undertaken as were mentioned for P-fimbriated E. coli.…”