Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers.
The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.
Griffin
John H
JH
Contribution from Theravance, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, USA. jgriffin@pharmix.com
Linsell
Martin S
MS
Nodwell
Matthew B
MB
Chen
QiQi
Q
Pace
John L
JL
Quast
Kelly L
KL
Krause
Kevin M
KM
Farrington
Lesley
L
Wu
Terry X
TX
Higgins
Deborah L
DL
Jenkins
Thomas E
TE
Christensen
Burton G
BG
Judice
J Kevin
JK
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D019281:Dimerization; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D014640:Vancomycin