Abstract
The article describes an NMR spectroscopy study of interactions between vancomycin and a muramyl pentapeptide in two complexes: vancomycin and a native muramyl pentapeptide ended with D-alanine (MPP-D-Ala), and vancomycin and a modified muramyl pentapeptide ended with D-serine (MPP-D-Ser). The measurements were made in a 9:1 mixture of H2O and D2O. The obtained results confirmed the presence of hydrogen bonds previously described in the literature. At the same time, thanks to the pentapeptide model used, we were able to prove the presence of two more hydrogen bonds formed by the side chain amino group of L-lysine and oxygen atoms from the vancomycin carboxyl and amide groups. This type of interaction has not been described before. The existence of these hydrogen bonds was confirmed by the 1H NMR and molecular modeling. The formation of these bonds incurs additional through-space interactions, visible in the NOESY spectrum, between the protons of the L-lysine amino group and a vancomycin-facing hydrogen atom in the benzylic position. The presence of such interactions was also confirmed by molecular dynamics trajectory analysis.
Highlights
Vancomycin is one of the most important glycoprotein antibiotics and, thanks to its effectiveness, it is often called a last resort antibiotic
The vancomycinmuramyl complex is stabilized by the hydrophobic van der Waals interactions and five hydrogen bonds formed between the L-lysine and subsequent two D-alanine residues, and the vancomycin binding pocket formed by the cyclic heptapeptide (Figure 1)
In our study on this mechanism, muramyl pentapeptide derivative, the synthesis, and characteristics of which we described weourdecided to use in earlier work
Summary
Vancomycin is one of the most important glycoprotein antibiotics and, thanks to its effectiveness, it is often called a last resort antibiotic. In the mid-1980s, vancomycin-resistant S. aureus (VRSA) [1,2,3] and vancomycin-resistant S. epidermidis (VRSE) [4,5] strains appeared The emergence of these vancomycin-resistant strains necessitates the search for new antibiotics that would be more effective in their treatment. In the case of vancomycin, the most likely mechanism is the formation of a complex of vancomycin with the last two D-alanine residues in muramyl pentapeptide sequence [6,7]. This blocks the possibility of peptidoglycan cross-linking and, the expansion of the cell wall of gram-positive bacteria. Bacteria have developed a defense mechanism involving the exchange of a
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