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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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Diaminopimelic moiety in the open peptidoglycan is shown.Pep-A stays for a D-alanine moiety, Pep-B for the D-glutamic moiety, Pep-C represents a cross-linked peptide. We are testing whether methylol derivatives of taurolidine (RCH2OH) attack the NH2 group to establish a NHCH2R terminal moiety as shown in Figure 7.
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pone-0008927-g006: Diaminopimelic moiety in the open peptidoglycan is shown.Pep-A stays for a D-alanine moiety, Pep-B for the D-glutamic moiety, Pep-C represents a cross-linked peptide. We are testing whether methylol derivatives of taurolidine (RCH2OH) attack the NH2 group to establish a NHCH2R terminal moiety as shown in Figure 7.

Mentions: The affinity of formaldehyde for NH2 groups of amino acids [28] and proteins [29], through its related methylol derivatives, is useful in vaccine production. Since taurolidine metabolism produces formaldehyde [30], we study the potential interaction of methylol-taurolidine derivatives with amino acids of peptidoglycan. In particular, our interest is focused upon the action of bacterial autolysin enzymes during the growth of the cell wall, when the dipeptide cross-linking involving the diaminopimelic moiety R′-(CH2)3-CHNHR″-C(O)-R′″ becomes temporarily cleaved. This results in formation of R′-(CH2)3-CHNH2C(O)-R″′ and HOR”. The opening of the cell wall is associated with a process needed for cell wall renovation by the arrival and insertion of new saccharide-pentapeptide units. We hypothesize that, as with formaldehyde, R-CH2OH methylol groups from taurolidine will interact with the NH2 group of R′-(CH2)3-CHNH2-C(O)-R″′ to form R′-(CH2)3-CHNHCH2R-C(O)-R″′; a related model for the open peptidoglycan is shown in Figure 6. In our quantum-mechanical study, we use a model derived from Figure 6, namely, Pep-A and Pep-B are replaced with H atoms and Pep-C with OH. The reaction involving this model is shown in Figure 7.


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)

Diaminopimelic moiety in the open peptidoglycan is shown.Pep-A stays for a D-alanine moiety, Pep-B for the D-glutamic moiety, Pep-C represents a cross-linked peptide. We are testing whether methylol derivatives of taurolidine (RCH2OH) attack the NH2 group to establish a NHCH2R terminal moiety as shown in Figure 7.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0008927-g006: Diaminopimelic moiety in the open peptidoglycan is shown.Pep-A stays for a D-alanine moiety, Pep-B for the D-glutamic moiety, Pep-C represents a cross-linked peptide. We are testing whether methylol derivatives of taurolidine (RCH2OH) attack the NH2 group to establish a NHCH2R terminal moiety as shown in Figure 7.
Mentions: The affinity of formaldehyde for NH2 groups of amino acids [28] and proteins [29], through its related methylol derivatives, is useful in vaccine production. Since taurolidine metabolism produces formaldehyde [30], we study the potential interaction of methylol-taurolidine derivatives with amino acids of peptidoglycan. In particular, our interest is focused upon the action of bacterial autolysin enzymes during the growth of the cell wall, when the dipeptide cross-linking involving the diaminopimelic moiety R′-(CH2)3-CHNHR″-C(O)-R′″ becomes temporarily cleaved. This results in formation of R′-(CH2)3-CHNH2C(O)-R″′ and HOR”. The opening of the cell wall is associated with a process needed for cell wall renovation by the arrival and insertion of new saccharide-pentapeptide units. We hypothesize that, as with formaldehyde, R-CH2OH methylol groups from taurolidine will interact with the NH2 group of R′-(CH2)3-CHNH2-C(O)-R″′ to form R′-(CH2)3-CHNHCH2R-C(O)-R″′; a related model for the open peptidoglycan is shown in Figure 6. In our quantum-mechanical study, we use a model derived from Figure 6, namely, Pep-A and Pep-B are replaced with H atoms and Pep-C with OH. The reaction involving this model is shown in Figure 7.

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