Multivalent Drug Design. Synthesis and In Vitro Analysis of an Array of Vancomycin Dimers

Abstract

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.

Multivalent Antibiotics via Metal Complexes: Potent Divalent Vancomycins against Vancomycin-Resistant Enterococci

“…Though other mechanisms cannot be ruled out at this moment, the above analysis supports the hypothesis of the roles of rigidity in divalency for the case of VanA and VanB strains. ∆S conf correlates, however, to little enhancement of the activity of dimeric Vans against vancomycin-sensitive strains and the less resistant VRE (VanC), which has been observed in other systems of divalent Vans, 16,17,34 suggesting the enhancement of the activity of dimeric Vans may depend on the composition of peptidoglycan precursors produced by the strains. 43 …”

“…According to this binding mode, both the configuration and rigidity of the dimeric Vans determine their activities. 34 To further understand the structuralactivity relationship, we performed semiquantitative entropy analysis according to the reported methods. 36 Let the conformational entropies (∆S conf ) of Van plus the CONHCH 2 segment to be the same as in 4-7, we compared the ∆S conf of the different linkers (green portions) upon dimerization (assuming the ∆S conf of the metal complex linker to be zero due to the rigidity of [Pt(en)] 2+ ).…”

“…25,26,28 Though Van self-associates to form homodimers upon binding to D-Ala-D-Ala, as elucidated by Williams et al, [29][30][31][32][33] this noncovalent dimerization of Van alone is insufficient to act against VRE. Griffin et al, 17,34 Nicolaou et al, 15,16,19,20 and an Eli Lilly group 35 have used organic linkers to synthesize dimers of Van, and demonstrated that covalently linked dimeric Vans exhibit enhanced to potent activity against VRE. It was, however, suggested that the flexibility of the organic linker limited the avidity of the multivalent binding due to the loss of conformational entropy upon binding.…”

Tuning the Activity of a Short Arg-Trp Antimicrobial Peptide by Lipidation of a C- or N-Terminal Lysine Side-Chain

“…For example, synergistic approaches can be explored using synthetic methods, as was shown by combination of vancomycin with nisin(1-12), 10 combination of vancomycin with metalloenzyme active site mimics, 11 and dimerization of vancomycin. 12 Importantly, even simple modifications can already lead to significant improvements and change the spectrum of activity, as was shown for lipidated vancomycin: the attachment of lipids to vancomycin led to a 40-fold increase in activity against vancomycin-resistant Enterococci (VRE). 13 A similar effect has been shown for (short) peptides, where attachment of lipids to the peptide N-terminus turned otherwise nonactive peptides into nontoxic AMPs with antifungal and antibacterial activity over a broad range of pathogens.…”

Rigid Multivalent Scaffolds Based on Adamantane

“…1 Chemists have made use of this concept in various contexts. [2][3][4][5][6][7][8][9] The binding ability of multivalent agents is influenced by the number, size and orientation of the binding sites, as well as the shape, orientation and flexibility of the scaffold to which monomeric ligands are attached. Theoretically, the largest gain of binding affinity for a given ligand-receptor interaction is expected for a perfect fit of the ligands to the binding epitope.…”