Hydrophobic Side-Chain Length Determines Activity and Conformational Heterogeneity of a Vancomycin Derivative Bound to the Cell Wall of Staphylococcus aureus

Biochemistry, 2008, 47 (38), pp 10155--10161

Disaccharide-modified glycopeptides with hydrophobic side chains are active against vancomycin-resistant enterococci and vancomycin-resistant Staphylococcus aureus. The activity depends on the length of the side chain. The benzyl side chain of N-(4-fluorobenzyl)vancomycin (FBV) has the minimal length sufficient for enhancement in activity against vancomycin-resistant pathogens. The conformation of FBV bound to the peptidoglycan in whole cells of S. aureus has been determined using rotational-echo double resonance NMR by measuring internuclear distances from the 19F of FBV to 13C and 15N labels incorporated into the cell-wall peptidoglycan. The hydrophobic side chain and aglycon of FBV form a cleft around the pentaglycyl bridge. FBV binds heterogeneously to the peptidoglycan as a monomer with the 19F positioned near the middle of the pentaglycyl bridge, approximately 7 A from the bridge link. This differs from the situation for N-(4-(4-fluorophenyl)benzyl)vancomycin complexed to the peptidoglycan where the 19F is located at the end of pentaglycyl bridge, 7 A from the cross-link.

Chemical structures of (A) chloroeremomycin, (B) N-(4-chlorobenzyl)chloroeremomycin (LY191145), (C) N-(4-(4-chlorophenyl)benzyl)chloroeremomycin (oritavancin), and (D) N-(4-fluorobenzyl)vancomycin (FBV). The latter differs from chlorobenzylchloroeremomycin by the absence of 4-epivancosamine at the sixth amino acid position of the aglycon structure and substitution of F for Cl in the hydrophobic side chain. Minimal inhibitory concentrations against vancomycin-resistant E. faecium are (A) 32 ug/mL, (B) 1 ug/mL, and (C) 0.5 ug/mL.

Molecular models of FPBV-PG (left), FBV-PG (middle), and vancomycin-PG (right) cell-wall complexes consistent with the REDOR results.

Schematic representation of the effect on cell-wall biosynthesis (A) of lipoglycopeptide binding to the mature peptidoglycan template (nearest strand to the membrane surface not connected to lipid II) (B), resulting in reductions in cross-linking from propagation of defective templates (C).