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Antimicrobial Agents and Chemotherapy, September 2005, p. 3842-3846, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3842-3846.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Effects of Soluble, Monovalent Globotriose on Bacterial Attachment and Colonization

James L. Leach,¹ Stacey A. Garber,² Andrea A. Marcon,¹ and Pedro A. Prieto^3*

Abbott Laboratories/Ross Products Division, Technology Assessment Department,¹ Abbott Laboratories/Ross Products Division, Glycobiology Department,² Abbott Laboratories, International Research and Development Department, 625 Cleveland Ave., Columbus, Ohio 43215³

Received 13 August 2004/ Returned for modification 3 January 2005/ Accepted 14 April 2005

Epithelial cells lining the urinary tract are rich in globo series glycolipids, structurally defined by a Gal1,4Gal motif in the oligosaccharide moiety of this glycolipid family. This Gal1,4Gal motif is the attachment target for the P-fimbrial adhesin of uropathogenic Escherichia coli. We investigated the ability of a trisaccharide analog of this core motif, globotriose (Gal1,4Galß1,4Glc), to interfere with uropathogen attachment and colonization in vitro and in vivo. We assessed the ability of globotriose to inhibit and reverse the binding and agglutination of a P-fimbriated strain of E. coli (JR1) using human erythrocytes and immortalized human colonic epithelial cells as targets. Globotriose (5 mg/ml) completely inhibited and reversed cell agglutination and caused a 10- to 100-fold reduction in JR1 binding to target cells, as determined by flow cytometry. In preparation for an in vivo efficacy study, we investigated the distribution and pharmacokinetics of globotriose in the BALB/c mouse. Globotriose was administered via the tail vein, targeting an instantaneous plasma concentration of 5 mg/ml, and in a different experiment, animals were gavaged at 10 times the intravenous (i.v.) dose. Globotriose was rapidly cleared from plasma (half-life [t_1/2], 6 min) and slowly excreted via the kidney (t_1/2, 4 h). Urine levels of >5 mg/ml were maintained from 4 to 12 h after the i.v. bolus dose, which resulted in a 1-log reduction in established bladder colonization by JR1. These results suggest that free, soluble globotriose is a feasible alternative therapy for urinary tract infections.

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* Corresponding author. Mailing address: Abbott Laboratories, International Research and Development Department, 625 Cleveland Ave., Columbus, OH 43215. Phone: (614) 624-3342. Fax: (614) 727-3342. E-mail: pedro.Prieto{at}abbott.com.

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Antimicrobial Agents and Chemotherapy, September 2005, p. 3842-3846, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3842-3846.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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