The Molecular and Crystal Structure of the Glycopeptide A‐40926 Aglycone

Abstract

The crystal structure of a glycopeptide antibiotic A40926 aglycone was investigated by X-ray analysis at -120O. A-40926 crystallises in the orthorhombic space group P2,2,2, with two monomers in the asymmetric unit, a = 21.774(4), b = 28.603(7), c = 29.757(4) A. 'Conventional' direct methods approach failed to solve the structure, but a novel iterative real/reciprocal space procedure was successful. Refinement against 1 1248 F2 data led to R 1 = 13.3 % for 6770 F > 4o(F). The two monomers of A-40926 have similar conformations and are bound by antiparallel H-bonds to form a 'chain' structure of connecting dimers. The antibiotic molecule possesses a 'binding pocket' for the C-terminal carboxy group of the cell-wall protein, which is consistent with suggestions based on NMR ddta and the recently reported crystal structure of ureido-balhimycin. In A-40926 the monomers are polymerically linked by H-bonds, quite unlike the tight dimer formation observed in ureido-balhimycin.

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics

“…In 1995, the first crystallographic analysis of an intact, naturally occurring glycopeptide antibiotic, balhimycin (7, Figure 7), was reported by Sheldrick et al [19] Soon thereafter followed the crystal structures of vancomycin [20] and the parvodicin aglycon (1996). [21] The structure of vancomycin bound to a surrogate ligand (acetate) was solved by X-ray crystallographic techniques in 1997 [22] and in 1998 the structure of vancomycin bound to N-acetate-d-alanine was solved, [23] which supported the proposed biological mechanism of action.…”

“…[19] A number of other X-ray structures have since followed, including those of vancomycin [20,22,23] and of the parvodicin aglycon. [21] 6. Synthetic Studies Synthetic studies in the area of glycopeptide antibiotics were initially slow, but have intensified rapidly in recent years.…”

Highlighting the role of the chlorine substituents in the glycopeptide antibiotic balhimycin for chiral recognition in capillary electrophoresis

“…It has been established for a long time that antibiotic activity of the vancomycin-type glycopeptide antibiotics rests on the high specificity of the aglycon cavity formed by cyclization of five aromatic side-chains towards the N-acetyl-D-Ala-D-Ala-peptide motif of bacterial cell-wall precursors [27,28]. The molecular bases for this binding are five hydrogen bonds, which have been extensively studied by (NMR) [28][29][30][31] and X-ray crystallography [32][33][34][35][36]. Three types of interactions between vancomycin-type antibiotics and D-Ala-D-Ala-terminating peptides have recently been confirmed: (1) the binding of the C-terminal carboxy- late of the D-Ala to the three-amide NH groups of the residues 2-4 of the peptide backbone; (2) the formation of two amide-amide hydrogen bonds between the N-Ac-DAla-D-Ala and the glycopeptide backbone and (3) the hydrophobic interactions of the alanine methyl residue with the aromatic side-chains of the glycopeptides.…”

Chemie, Biologie und medizinische Anwendungen der Glycopeptid-Antibiotika

“…Sheldrick et al gelang 1995 die erste Röntgenstrukturanalyse eines intakten natürlich vorkommenden Glycopeptid-Antibiotikums, des Balhimycins 7 (Abbildung 7). [19] 1996 wurden auch die Röntgenstrukturanalysen von Vancomycin [20] und dem Parvodicin-Aglycon [21] beschrieben. Die Struktur von Vancomycin mit Acetat als Ligand wurde 1997 durch eine Röntgenstrukturanalyse aufgeklärt und 1998 die Struktur von Vancomycin, gebunden an N-Acetyl-d-alanin.…”

“…[19] Eine Reihe anderer Röntgenstrukturanalysen folgte in der Zwischenzeit, auch die des Vancomycins [20,22,23] und des Parvodicin-Aglycons. [21] 6. Synthesestudien Die präparativen Arbeiten auf dem Gebiet der Glycopeptid-Antibiotika verliefen ursprünglich langsam, wurden aber in den vergangenen Jahren deutlich intensiviert.…”