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Taurolidine antiadhesive properties on interaction with E. coli; its transformation in biological environment and interaction with bacteria cell wall.

Caruso F, Darnowski JW, Opazo C, Goldberg A, Kishore N, Agoston ES, Rossi M - PLoS ONE (2010)

Bottom Line: To understand the taurolidine antibacterial mechanism of action, we provide the experimental single crystal X-ray diffraction results together with theoretical methods to characterize the hydrolysis/decomposition reactions of taurolidine.Taurolidine in a biological environment exists in equilibrium with taurultam derivatives and this is described theoretically as a 2-step process without an energy barrier: formation of cationic taurolidine followed by a nucleophilic attack of O(hydroxyl) on the exocyclic C(methylene).A concerted mechanism describes the further hydrolysis of the taurolidine derivative methylol-taurultam.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Rome, Italy. caruso@vassar.edu

ABSTRACT
The taurine amino-acid derivative, taurolidine, bis-(1,1-dioxoperhydro-1,2,4-thiabiazinyl-4)methane, shows broad antibacterial action against gram-positive and gram-negative bacteria, mycobacteria and some clinically relevant fungi. It inhibits, in vitro, the adherence of Escherichia coli and Staphylococcus aureus to human epithelial and fibroblast cells. Taurolidine is unstable in aqueous solution and breaks down into derivatives which are thought to be responsible for the biological activity. To understand the taurolidine antibacterial mechanism of action, we provide the experimental single crystal X-ray diffraction results together with theoretical methods to characterize the hydrolysis/decomposition reactions of taurolidine. The crystal structure features two independent molecules linked through intermolecular H-bonds with one of them somewhat positively charged. Taurolidine in a biological environment exists in equilibrium with taurultam derivatives and this is described theoretically as a 2-step process without an energy barrier: formation of cationic taurolidine followed by a nucleophilic attack of O(hydroxyl) on the exocyclic C(methylene). A concerted mechanism describes the further hydrolysis of the taurolidine derivative methylol-taurultam. The interaction of methylol-taurultam with the diaminopimelic NH(2) group in the E. coli bacteria cell wall (peptidoglycan) has a negative DeltaG value (-38.2 kcal/mol) but a high energy barrier (45.8 kcal/mol) suggesting no reactivity. On the contrary, taurolidine docking into E. coli fimbriae protein, responsible for bacteria adhesion to the bladder epithelium, shows it has higher affinity than mannose (the natural substrate), whereas methylol-taurultam and taurultam are less tightly bound. Since taurolidine is readily available because it is administered in high doses after peritonitis surgery, it may successfully compete with mannose explaining its effectiveness against bacterial infections at laparoscopic lesions.

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Similar structural features of taurolidine and mannose.Left: E. coli FimH protein showing a mannose guest at the active site. Right: overlap of single crystal deoxy-mannose molecule [41] (stick display) and one of the 4 taurolidine molecules found in the unit cell. H atoms bound to C in deoxy-mannose are omitted for clarity.
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pone-0008927-g010: Similar structural features of taurolidine and mannose.Left: E. coli FimH protein showing a mannose guest at the active site. Right: overlap of single crystal deoxy-mannose molecule [41] (stick display) and one of the 4 taurolidine molecules found in the unit cell. H atoms bound to C in deoxy-mannose are omitted for clarity.

Mentions: The FimH crystal structure with a mannose bound at the active site on the surface of the protein [40], is shown in Figure 10 (code 1KLF in the Protein Databank). We superimpose the crystal structure of deoxy-mannose [41] with each of the 4 molecules found in the unit cell of taurolidine, the two independent molecules and their corresponding inverted molecules. A ring of one of these taurolidine molecules shows excellent overlap with mannose; this is also depicted in Figure 10.


Taurolidine antiadhesive properties on interaction with E. coli; its transformation in biological environment and interaction with bacteria cell wall.

Caruso F, Darnowski JW, Opazo C, Goldberg A, Kishore N, Agoston ES, Rossi M - PLoS ONE (2010)

Similar structural features of taurolidine and mannose.Left: E. coli FimH protein showing a mannose guest at the active site. Right: overlap of single crystal deoxy-mannose molecule [41] (stick display) and one of the 4 taurolidine molecules found in the unit cell. H atoms bound to C in deoxy-mannose are omitted for clarity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2812514&req=5

pone-0008927-g010: Similar structural features of taurolidine and mannose.Left: E. coli FimH protein showing a mannose guest at the active site. Right: overlap of single crystal deoxy-mannose molecule [41] (stick display) and one of the 4 taurolidine molecules found in the unit cell. H atoms bound to C in deoxy-mannose are omitted for clarity.
Mentions: The FimH crystal structure with a mannose bound at the active site on the surface of the protein [40], is shown in Figure 10 (code 1KLF in the Protein Databank). We superimpose the crystal structure of deoxy-mannose [41] with each of the 4 molecules found in the unit cell of taurolidine, the two independent molecules and their corresponding inverted molecules. A ring of one of these taurolidine molecules shows excellent overlap with mannose; this is also depicted in Figure 10.

Bottom Line: To understand the taurolidine antibacterial mechanism of action, we provide the experimental single crystal X-ray diffraction results together with theoretical methods to characterize the hydrolysis/decomposition reactions of taurolidine.Taurolidine in a biological environment exists in equilibrium with taurultam derivatives and this is described theoretically as a 2-step process without an energy barrier: formation of cationic taurolidine followed by a nucleophilic attack of O(hydroxyl) on the exocyclic C(methylene).A concerted mechanism describes the further hydrolysis of the taurolidine derivative methylol-taurultam.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Rome, Italy. caruso@vassar.edu

ABSTRACT
The taurine amino-acid derivative, taurolidine, bis-(1,1-dioxoperhydro-1,2,4-thiabiazinyl-4)methane, shows broad antibacterial action against gram-positive and gram-negative bacteria, mycobacteria and some clinically relevant fungi. It inhibits, in vitro, the adherence of Escherichia coli and Staphylococcus aureus to human epithelial and fibroblast cells. Taurolidine is unstable in aqueous solution and breaks down into derivatives which are thought to be responsible for the biological activity. To understand the taurolidine antibacterial mechanism of action, we provide the experimental single crystal X-ray diffraction results together with theoretical methods to characterize the hydrolysis/decomposition reactions of taurolidine. The crystal structure features two independent molecules linked through intermolecular H-bonds with one of them somewhat positively charged. Taurolidine in a biological environment exists in equilibrium with taurultam derivatives and this is described theoretically as a 2-step process without an energy barrier: formation of cationic taurolidine followed by a nucleophilic attack of O(hydroxyl) on the exocyclic C(methylene). A concerted mechanism describes the further hydrolysis of the taurolidine derivative methylol-taurultam. The interaction of methylol-taurultam with the diaminopimelic NH(2) group in the E. coli bacteria cell wall (peptidoglycan) has a negative DeltaG value (-38.2 kcal/mol) but a high energy barrier (45.8 kcal/mol) suggesting no reactivity. On the contrary, taurolidine docking into E. coli fimbriae protein, responsible for bacteria adhesion to the bladder epithelium, shows it has higher affinity than mannose (the natural substrate), whereas methylol-taurultam and taurultam are less tightly bound. Since taurolidine is readily available because it is administered in high doses after peritonitis surgery, it may successfully compete with mannose explaining its effectiveness against bacterial infections at laparoscopic lesions.

Show MeSH
Related in: MedlinePlus