Efficacy of the antiadhesin octyl O-(2-acetamido-2-deoxy-beta-D-galactopyranosyl)-(1-4)-2-O-propyl-beta-D-galactopyranoside (Fimbrigal-P) in a rat oral candidiasis model.
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Journal: 2005/August - Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804
Abstract:
Adherence of Candida albicans to buccal epithelial cells via its fimbrial subunit requires the minimal disaccharide sequence beta-GalNAc(1-4)-beta-galactosidase in host cell receptors asialo-GM1 or asialo-GM2. This and other disaccharides and some of its synthetic derivatives have been shown to inhibit purified fimbrial or pathogen binding in vitro. This study evaluates the in vivo efficacy of the propyl derivative of this disaccharide, octyl O-(2-acetamido-2-deoxy-beta-D-galactopyranosyl)-(1-4)-2-O-propyl-beta-D-galactopyranoside, or Fimbrigal-P, incorporated into a mucoadhesive polymer formulation in a rat oral candidiasis model. Colony counts of microcurette samples from the oral cavity and tongue homogenates were used to estimate the effectiveness of four treatment modalities to reduce oral fungal burden. All treatment modalities (preventative, premixing with the Candida inoculant, drinking water, and treatment) significantly reduced fungal burden compared to untreated control animals by day 9; however, the preventative and pre-mixing approaches provided a faster rate of fungal clearance. The low toxicity and immunogenicity of this synthetic carbohydrate and its stability in saliva, as demonstrated by high-performance liquid chromatography, make it a promising candidate for the prevention and treatment of microbial infections in which the pathogen relies on the beta-GalNAc(1-4)-beta-galactosidase disaccharide to establish adherence.
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Antimicrob Agents Chemother 49(7): 2887-2894
PMID: 15980365

Efficacy of the Antiadhesin Octyl <em>O</em>-(2-Acetamido-2-Deoxy-β-<span class="small-caps">d</span>- Galactopyranosyl)-(1-4)-2-<em>O</em>-Propyl-β-<span class="small-caps">d</span>-Galactopyranoside (Fimbrigal-P) in a Rat Oral Candidiasis Model

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada, Department of Pathology, McMaster University, Hamilton, Ontario, Canada, Helix BioPharma Corp., Aurora, Ontario, Canada3
Corresponding author. Mailing address: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. Phone: (306) 966-6338. Fax: (306) 966-6377. E-mail: ac.ksasu.ekud@iravdlof.
Present address: School of Pharmacy and Bu-Ali Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Received 2004 May 5; Revised 2004 Jul 11; Accepted 2005 Jan 16.
Copyright © 2005, American Society for Microbiology

Abstract

Adherence of Candida albicans to buccal epithelial cells via its fimbrial subunit requires the minimal disaccharide sequence β-GalNAc(1-4)-β-galactosidase in host cell receptors asialo-GM1 or asialo-GM2. This and other disaccharides and some of its synthetic derivatives have been shown to inhibit purified fimbrial or pathogen binding in vitro. This study evaluates the in vivo efficacy of the propyl derivative of this disaccharide, octyl O-(2-acetamido-2-deoxy-β-d-galactopyranosyl)-(1-4)-2-O-propyl-β-d-galactopyranoside, or Fimbrigal-P, incorporated into a mucoadhesive polymer formulation in a rat oral candidiasis model. Colony counts of microcurette samples from the oral cavity and tongue homogenates were used to estimate the effectiveness of four treatment modalities to reduce oral fungal burden. All treatment modalities (preventative, premixing with the Candida inoculant, drinking water, and treatment) significantly reduced fungal burden compared to untreated control animals by day 9; however, the preventative and premixing approaches provided a faster rate of fungal clearance. The low toxicity and immunogenicity of this synthetic carbohydrate and its stability in saliva, as demonstrated by high-performance liquid chromatography, make it a promising candidate for the prevention and treatment of microbial infections in which the pathogen relies on the β-GalNAc(1-4)-β-galactosidase disaccharide to establish adherence.

Abstract

As conventional antibiotics become less effective due to increasing resistance, alternative means of preventing and eradicating infections must be developed. Because the ability to adhere to host cells is directly related to the potential infectivity of a microorganism (2), one promising approach may involve the prevention of microbial adhesion to host cells by blocking the attachment of microbial appendages known as pili or fimbriae to their cellular receptors (14, 27). These structures are a feature of many gram-negative bacteria such as Pseudomonas aeruginosa, Helicobacter pylori, and Escherichia coli, as well as fungi such as Candida albicans (3, 4, 10, 19).

C. albicans is a dimorphic yeast capable of causing opportunistic infections ranging from topical to systemic, particularly in immunocompromised individuals. C. albicans contains a fimbrial subunit, a major component of the fungal fimbria, which is responsible for adherence to the host cell surface. The adherence of C. albicans to host cells in the oral cavity appears to be a two-step process. After the initial fimbria-mediated binding, the hyphae invade the mucosal surface and initiate an inflammatory process (13, 22). Recently, several genes (HWP1, ALS1, ALA1, and INT1) were identified that encode proteins with adherent properties (7-9, 12, 21). The adherence may involve lectin, protein-protein, or hydrophobic interactions (5).

A Candida fimbrial adhesin (MP66) has been identified and partially characterized to be a hydrophobic mannoprotein with a mature molecular mass of 66 kDa, of which 85% is carbohydrate and 15% is protein (24). This molecule mediates fungal adhesion to human buccal epithelial cells (BEC) via an interaction with asialo-GM1 and asialo-GM2 glycolipids on the host cell surface (25). Binding to these host cell receptors occurs via the carbohydrate moiety of the glycolipids, as synthetic disaccharides have been shown to competitively inhibit in vitro BEC binding by C. albicans (25). The minimum domain required for binding to BEC asialo-GM1 and asialo-GM2 is the disaccharide βGalNAc (1-4)-βGal [octyl O-(2-acetamido-2-deoxy-β-d-galactopyranosyl)-(1-4) β-d-galactopyranoside](18). The receptor-binding domain of the C. albicans adhesin is conserved with that of P. aeruginosa, and synthetic derivatives of this disaccharide can also competitively inhibit the binding of this bacterium to immobilized asialo-GM1 in vitro (15, 24, 25). The propyl derivative of the disaccharide appears to be particularly effective, with a pathogen-binding affinity 10-fold higher than that of the native receptor analogue (17). In this study, we present results evaluating the therapeutic efficacy of Fimbrigal-P (Fig. ​(Fig.1)1) in an in vivo rat oral candidiasis model.

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Octyl O-(2-acetamido-2-deoxy-β-d-galactopyranosyl)-(1-4)-2-O-propyl-β-d-galactopyranoside (Fimbrigal-P) is one of a family of compounds based on the β-GalNAc(1-4)-β-galactosidase disaccharide structure.

Acknowledgments

We thank W. Y. Wong, R. T. Irvin, O. Hindsgaul, and R. Hodges, Department of Medical Microbiology and Infectious Diseases, University of Alberta, Protein Engineering Network Centers of Excellence (PENCE) Edmonton, Alberta, Canada, for providing the compound Fimbrigal-P.

Acknowledgments

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