“…This was first discovered in vancomycin in the late 1960s and then confirmed by NMR studies by the Williams group in 1983 126. More recently, these results have been confirmed by X‐ray crystallography 127, 128, 129. The resulting steric hindrance from this binding inhibits the transglycosylation and transpeptidation steps in cell wall synthesis ultimately resulting in bacterial cell death (Figure 26).…”
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
“…This was first discovered in vancomycin in the late 1960s and then confirmed by NMR studies by the Williams group in 1983 126. More recently, these results have been confirmed by X‐ray crystallography 127, 128, 129. The resulting steric hindrance from this binding inhibits the transglycosylation and transpeptidation steps in cell wall synthesis ultimately resulting in bacterial cell death (Figure 26).…”
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
“…The formation of large-scale aggregates has been proposed to be important for antimicrobial activity [12]. Specifically, a decrease in the propensity to form face-to-face dimers, and thus the ability to form stable large-scale aggregates, has been proposed to explain (at least in part) why the D-Ala-DLac variant of lipid II leads to vancomycin resistance in vivo [12]. A possible role for face-to-face dimer formation in glycopeptide activity is also suggested if one compares the minimum inhibitory concentration values of vancomycin, THRX-689909 and telavancin.…”
Section: Discussionmentioning
confidence: 99%
“…7, the face-to-face dimer had C2-symmetry and was stabilized by four hydrogens. Two involved interactions between the phenyl hydroxyl hydrogen of LPGH7 of one vancomycin with the C-terminal carboxyl oxygen of the ligand bound to the other vancomycin, and two were interactions between the backbone of the two ligands [12,17]. Although NMR data suggest that the back-to-back dimer is the predominate form in solution, the crystal structures suggest that other packing arrangements are also possible.…”
Section: Dimer Formationmentioning
confidence: 99%
“…Lipid II is insoluble in water and thus most investigations of the recognition of lipid II by vancomycin have involved either chemically modified or truncated fragments of lipid II [10]. NMR and X-ray crystallographic studies [11][12][13][14][15][16][17] showed that the ligand bound to the concave (front face) of vancomycin, the C-terminal carboxylic acid group of D-Ala-D-Ala interacting with the backbone amide groups of resides NLEU1, HDPY2 and ASN3. In addition, the amide group of Ala1 forms a stable hydrogen bond with the carbonyl oxygen of DPYG4.…”
The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance.
“…The mechanism of action is mainly through interactions in the biosynthesis of bacteria cell wall. A number of D-Ala-D-Ala related peptides in complex with such glycopeptide antibiotics are available in the literature, not only for ristocetin-A [1] but also for vancomycin [2], balhimycin [3], or chloroorienticin-A [4]. Some of them were reported in complex with a protein implicated in their biosynthesis like teicoplanin [5].…”
Ristocetin-A belongs to the group of the glycoheptapeptide antibiotics. The sulfate salt of ristocetin-A was crystallized in the P2 1 monoclinic space group with a homodimer in the asymmetric unit. The two subunits are linked back-to-back like the other members of the family via four peptide bonds forming a twisted -sheet and exposing the binding pockets to the exterior. The two tetrasaccharide parts of this ligand-free antibiotic are in the anti/anti orientations contrary to what was found in the monoand diliganded ristocetin-A/-(D-Ala-D-Ala) complexes in which the two tetrasaccharides of the dimer are syn/anti. The ligand-free dimer shows however some conformational differences between the two subunits, particularly in the terminal arabinose leading to one extended and one bent conformation of the tetrasaccharide moiety. Comparison between this structure and the two available mono-and diliganded structures confirms that the anti/anti to syn/anti flipping of the tetrasaccharide is a key step in the binding to the D-Ala-D-Ala-containing target sequence and cannot proceed without displacement of the monomer/dimer equilibrium.
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