Cleavage of rhamnose from ristocetin A removes its ability to induce platelet aggregation

Bardsley, Ben; Dh, Williams; Tp, Baglin

doi:10.1097/00001721-199804000-00004

Cited by 10 publications

(15 citation statements)

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“…Fixed platelets (3 ϫ10 8 /ml) were washed twice with PBS and incubated with bacterial cell wall polysaccharide extracts of Xc or control strain Xc24R at various concentrations at 37°C for 1 h. After incubation, platelets were washed twice in PBS and incubated with rabbit anti-S. mutans serotype c polysaccharide rabbit IgG (10 g/ml) on ice for 40 min (7). Platelets were then washed and incubated with FITC-conjugated goat F(abЈ) 2 …”

Section: Methodsmentioning

confidence: 99%

Platelet Aggregation Induced by Serotype Polysaccharides fromStreptococcus mutans

et al. 2004

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Platelet aggregation plays an important role in the pathogenesis of infective endocarditis induced by viridans streptococci or staphylococci. Aggregation induced in vitro involves direct binding of bacteria to platelets through multiple surface components. Using platelet aggregometry, we demonstrated in this study that two Streptococcus mutans laboratory strains, GS-5 and Xc, and two clinical isolates could aggregate platelets in an irreversible manner in rabbit platelet-rich plasma preparations. The aggregation was partially inhibited by prostaglandin I 2 (PGI 2 ) in a dose-dependent manner. Whole bacteria and heated bacterial cell wall extracts were able to induce aggregation. Cell wall polysaccharides extracted from the wild-type Xc strain, containing serotype-specific polysaccharides which are composed of rhamnose-glucose polymers (RGPs), could induce platelet aggregation in the presence of plasma. Aggregation induced by the serotype-specific RGP-deficient mutant Xc24R was reduced by 50% compared to the wild-type strain Xc. In addition, cell wall polysaccharides extracted from Xc24R failed to induce platelet aggregation. The Xc strain, but not the Xc24R mutant, could induce platelet aggregation when preincubated with plasma. Both Xc and Xc24R failed to induce platelets to aggregate in plasma depleted of immunoglobulin G (IgG), but aggregation was restored by replenishment of anti-serotype c IgG. Analysis by flow cytometry showed that S. mutans RGPs could bind directly to rabbit and human platelets. Furthermore, cell wall polysaccharides extracted from the Xc, but not the Xc24R, strain could induce pseudopod formation of both rabbit and human platelets in the absence of plasma. Distinct from the aggregation of rabbit platelets, bacterium-triggered aggregation of human platelets required a prolonged lag phase and could be blocked completely by PGI 2 . RGPs also trigger aggregation of human platelets in a donor-dependent manner, either as a transient and reversible or a complete and irreversible response. These results indicated that serotype-specific RGPs, a soluble product of S. mutans, could directly bind to and activate platelets from both rabbit and human. In the presence of plasma containing IgG specific to RGPs, RGPs could trigger aggregation of both human and rabbit platelets, but the degree of aggregation in human platelets depends on the donors.

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Section: Methodsmentioning

confidence: 99%

Platelet Aggregation Induced by Serotype Polysaccharides fromStreptococcus mutans

et al. 2004

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“…In spite of its good antibacterial activity against Gram-positive strains including MRSA, 2 this antibiotic has not been used in therapy due to its ability to cause aggregation of blood platelets. 3 Williams et al reported 4 that cleavage of Lrhamnose from ristocetin A removes this aggregating property. In a systematic study with aglyco-ristocetin 5 (2) (Scheme 1) derivatives we found that deglycosylation of 1 retains the antibacterial activity, however 2 is not suitable for platelet aggregation tests due to its very low solubility in water.…”

Section: Introductionmentioning

confidence: 99%

Click reaction synthesis of carbohydrate derivatives from ristocetin aglycon with antibacterial and antiviral activity

Pintér

Bereczki

Batta

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tNew sugar derivatives of ristocetin were prepared by copper-catalyzed 1,3-dipolar cycloaddition reaction using azido-ristocetin aglycon and various propargyl glycosides. Some of them were found to be active against Gram-positive bacteria and showed favorable antiviral activity against the H1N1 subtype of influenza A virus.Ó 2010 Elsevier Ltd. All rights reserved. rhamnose from ristocetin A removes this aggregating property. In a systematic study with aglyco-ristocetin 5 (2) (Scheme 1) derivatives we found that deglycosylation of 1 retains the antibacterial activity, however 2 is not suitable for platelet aggregation tests due to its very low solubility in water. To improve solubility, we prepared derivatives of 2 containing b-D-glucopyranosyl and b-Dmaltosyl substituents attached through an N-glycosylthiourea moiety. 6 These derivatives possessed good antibacterial activity and did not induce platelet aggregation. These promising results prompted us to perform a systematic study on the influence of various sugar substituents on the biological activity of derivatives of 2. In this work we here report on the synthesis and biological activity of several new sugar derivatives of 2. For conjugation of 1 we have chosen D-glucose, D-mannose and L-rhamnose, since the ristocetin molecule also contains these saccharides. Another glycopeptide antibiotic, teicoplanin has N-acetyl-D-glucosamine substituent, consequently this sugar was also chosen for the derivatisation of 1. Following our diazo-transfer-click reaction sequence 7 3 was chosen as the starting compound. Copper-catalyzed 1,3-dipolar cycloaddition reaction ('click reaction') 8 of the latter with per-O-acetylated propargyl glycosides 9 resulted in the carbohydrate-substituted aglycons 4a-8a. Zemplén deacetylation 10 of the sugar acetate moieties led to the glycosyl-oxymethyl-triazolyl derivatives of the ristocetin aglycon carrying saccharides with a-D-Evaluation of the biological properties of these derivatives (including the per-O-acetates) against Gram-positive bacteria demonstrated that introduction of the sugar moieties at the N-terminus into the ristocetin A aglycon molecule had a beneficial effect on the antibacterial activity. From an analysis of the data summarized in Table 1, it can be seen that the most of the new derivatives displayed higher activity than 1. The sugar derivatives 4-7 had good to excellent bacteriostatic activity against the test organisms, including glycopeptide-resistant enterococci. Interestingly, in this small group of compounds, the configuration of the sugar part (D-sugars) exhibited only a slight influence on the MIC values.0960-894X/$ -see front matter Ó

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“…The mechanism of ristocetin induced agglutination of platelets involves vWf binding to platelet GPIbα. Cleavage of the rhamnose tetrasaccharide of ristocetin abolished its ability to induce platelet aggregation (Bardsley et al, 1998). Moreover, S. sanguinis expresses a platelet associated aggregating protein (PAAP) which is another rhamnose polymer which is thought to be involved in inducing platelet aggregation.…”

Section: Bacteriamentioning

confidence: 99%

Platelet-Bacterial Interactions as Therapeutic Targets in Infective Endocarditis

Kerrigan¹,

Cox²

2012

Endocarditis

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Cleavage of rhamnose from ristocetin A removes its ability to induce platelet aggregation

Cited by 10 publications

References 0 publications

Platelet Aggregation Induced by Serotype Polysaccharides fromStreptococcus mutans

Platelet Aggregation Induced by Serotype Polysaccharides fromStreptococcus mutans

Click reaction synthesis of carbohydrate derivatives from ristocetin aglycon with antibacterial and antiviral activity

Platelet-Bacterial Interactions as Therapeutic Targets in Infective Endocarditis

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