Figure 1.
Hydrolysis/decomposition of taurolidine.
Figure 2.
Molecular structure of the 2 independent molecules of taurolidine in the asymmetric unit of the crystal.
Figure 3.
The approach of OH− towards cationic taurolidine.
Atoms involved in a potential transition state (TS) are wireframe style; S = yellow, N = blue, C = grey, H = white.
Figure 4.
Geometry optimization for OH− attack on cationic taurolidine.
This is performed with DMol3 in Materials Studio: initial (left) and final (right) states.
Figure 5.
A concerted mechanism of taurultam hydrolysis.
Initial state (left), final state yielding methylol-taurineamide, (center), and the transition state (right).
Figure 6.
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.
Figure 7.
Theoretically studied reaction of a taurolidine-methylol derivative RCH2OH and the pimelic NH2 group in open peptidoglycan.
Figure 8.
Transition state for condensation between methylol-taurultam and a diaminopimelic acid model implying water release.
Figure 9.
Formaldehyde hydration equilibrium.
Figure 10.
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.
Figure 11.
Stick display of taurolidine and its derivatives, methylol taurultam and taurultam, at the active site of E. coli FimH.
Top left: taurolidine with H-bond interacting amino acids and water (ball and spoke display) shows the formation of a 6-membered ring -H-N(phe1)-H-O(sulfonyl)-S-N(taur)-; the non interacting taurolidine ring protrudes outside the protein pocket. Top right: methylol taurultam shows 4 H-bonds: (a) S(sulfonyl) as a hydrogen bond acceptor from the NH3-(Phe1), (b) O–H acts as a bifurcated hydrogen bond donor to O(carbonyl) of Arg46 and Phe1, (c) O(hydroxyl)as a hydrogen bond acceptor from HN-(Asp47). Bottom: taurultam also has 4 hydrogen bonds: (a) O(sulfonyl) as a hydrogen bond acceptor from two hydrogens of NH3-(Phe1), (b) N-H as hydrogen bond donor to O(carbonyl)-(Asp54) and (c) hydrogen bond acceptor from H-N-(Asn135).
Figure 12.
H-bond interaction of taurolidine and mannose at the FimH active site.
Both molecules establish a double H-bond with NH3 of Phe1, e.g. a 6-membered ring for taurolidine (left, ball and stick style) and a 10-membered ring for mannose (left, C-NH3 moiety of Phe1, ball and stick style). For clarity, Phe1 is the only amino acid shown in the left figure (line style except for NH2), and only the C-NH3 moiety of Phe1 is shown for mannose on the right.
Table 1.
Energy (kcal/mol) data for guests in the pocket of E. coli fimbriae protein active site.
Table 2.
Crystal data and refinement details of taurolidine, C7H16N4O4S2.