Vancomycin-Ligand Complexes. P. J. Loll, J. Kaplan, P. H. Axelsen, Dept. of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19143
Vancomycin is a "last-resort" antibiotic used to treat serious bacterial infections resistant to more common antibiotics. Unfortunately, resistance to vancomycin has emerged and is spreading at an alarming rate. e. g., fully 25% of all enterococci isolated at U. Penn. in 1996 were completely resistant to vancomycin. No reliable treatment options exist in such cases.
Vancomycin binds a peptide chain terminating in D-alanine-D-alanine which is formed as an intermediate in bacterial cell wall biosynthesis. The most common vancomycin resistance phenotype alters this sequence to D-alanine-D-lactate; this change from the amide to the ester ablates vancomycin binding. We are using a combination of crystallographic, spectroscopic, and modeling methods to understand the recognition of various ligands by vancomycin, with the aim of designing novel therapeutic agents to address the emerging threat of resistant microorganisms.
As is true for many "large small molecules," the structure solution of vancomycin was hampered by a large unit cell (5 x 104 Å3; ca. 300 unique non-hydrogen atoms) containing a high percentage of poorly ordered solvent. The structure of the vancomycin:acetate complex has recently been solved, using synchrotron radiation and ab initio phasing methods that employ iterative real space/reciprocal space recycling1,2. We report here structures for complexes of vancomycin with several larger ligands, and discuss their significance for the recognition of physiologically relevant targets.
1. Schäfer, M., Schneider, T. R., & Sheldrick, G. M. (1996) Structure 4: 1509-1515.
2. Loll, P. J., Bevivino, A. E., Korty, B. D., & Axelsen, P. H. (1997) J. Am. Chem. Soc. 119: 1516-1522.