Crystal structures of the complexes between vancomycin and cell-wall precursor analogs.
The crystal structures of three vancomycin complexes with two vancomycin-sensitive cell-wall precursor analogs (diacetyl-Lys-D-Ala-D-Ala and acetyl-D-Ala-D-Ala) and a vancomycin-resistant cell-wall precursor analog (diacetyl-Lys-D-Ala-D-lactate) were determined at atomic resolutions of 1.80 A, 1.07 A, and 0.93 A, respectively. These structures not only reconfirm the "back-to-back" dimerization of vancomycin monomers and the ligand-binding scheme proposed by previous experiments but also show important structural features of strategies for the generation of new glycopeptide antibiotics. These structural features involve a water-mediated antibiotic-ligand interaction and supramolecular structures such as "side-by-side" arranged dimer-to-dimer structures, in addition to ligand-mediated and "face-to-face" arranged dimer-to-dimer structures. In the diacetyl-Lys-D-Ala-D-lactate complex, the interatomic O...O distance between the carbonyl oxygen of the fourth residue of the antibiotic backbone and the ester oxygen of the D-lactate moiety of the ligand is clearly longer than the corresponding N-H...O hydrogen-bonding distance observed in the two other complexes due to electrostatic repulsion. In addition, two neighboring hydrogen bonds are concomitantly lengthened. These observations provide, at least in part, a molecular basis for the reduced antibacterial activity of vancomycin toward vancomycin-resistant bacteria with cell-wall precursors terminating in -D-Ala-D-lactate.
Nitanai
Yasushi
Y
Structural Biophysics Laboratory, RIKEN SPring-8 Center, Harima Institute, Sayo, Hyogo, Japan. nitanai@spring8.or.jp
Kikuchi
Takanori
T
Kakoi
Kouji
K
Hanamaki
Shinji
S
Fujisawa
Ikuhide
I
Aoki
Katsuyuki
K
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001419:Bacteria / Q000737:chemistry; D002473:Cell Wall / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004151:Dipeptides / Q000737:chemistry*; D024881:Drug Resistance, Bacterial; D006860:Hydrogen Bonding; D007773:Lactates / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D014640:Vancomycin / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D007773:Lactates; D009842:Oligopeptides; C043631:diacetyllysylalanine lactate; C033530:N(alpha), N-(epsilon)-diacetyl-lysyl-alanyl-alanine; D014640:Vancomycin