Dendrimer-Based Multivalent Vancomycin Nanoplatform for Targeting the Drug-Resistant Bacterial Surface

Abstract

Vancomycin represents the preferred ligand for bacteria-targeting nanosystems. However, it is inefficient for emerging vancomycin-resistant species because of its poor affinity to the reprogrammed cell wall structure. This study demonstrates the use of a multivalent strategy as an effective way for overcoming such an affinity limitation in bacteria targeting. We designed a series of fifth generation (G5) poly(amidoamine) (PAMAM) dendrimers tethered with vancomycin at the C-terminus at different valencies. We performed surface plasmon resonance (SPR) studies to determine their binding avidity to two cell wall models, each made with either a vancomycin-susceptible (D)-Ala-(D)-Ala or vancomycin-resistant (D)-Ala-(D)-Lac cell wall precursor. These conjugates showed remarkable enhancement in avidity in the cell wall models tested, including the vancomycin-resistant model, which had an increase in avidity of four to five orders of magnitude greater than free vancomycin. The tight adsorption of the conjugate to the model surface corresponded with its ability to bind vancomycin-susceptible Staphylococcus aureus bacterial cells in vitro as imaged by confocal fluorescent microscopy. This vancomycin platform was then used to fabricate the surface of iron oxide nanoparticles by coating them with the dendrimer conjugates, and the resulting dendrimer-covered magnetic nanoparticles were demonstrated to rapidly sequester bacterial cells. In summary, this article investigates the biophysical basis of the tight, multivalent association of dendrimer-based vancomycin conjugates to the bacterial cell wall, and proposes a potential new use of this nanoplatform in targeting Gram-positive bacteria.

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Nanoparticle targeting of Gram-positive and Gram-negative bacteria for magnetic-based separations of bacterial pathogens

“…Targeting ligands include vancomycin which targets peptidoglycans found on Grampositive bacteria, polymyxin which targets lipopolysaccharides found on Gram-negative bacteria, or zinc(II)-bis(dipicolylamine) (ZnDPA) which targets phosphatidylserine found on the surface of both Gram-positive and Gram-negative bacteria (Choi et al 2013;Hanshaw and Smith 2005;Kell et al 2008;Wong et al 2015). Importantly, these ligand targets are not found on the surface of healthy mammalian cells, which allows for specific binding and imaging of bacteria with minimal background signals when using these targeting ligands in vivo (Rice et al 2015;van Oosten et al 2013).…”

Diffusion NMR Study of Generation-Five PAMAM Dendrimer Materials

“…4−8 G5 PAMAM is particularly interesting for biological applications because of its size, which is large enough to solubilize multiple hydrophobic entities yet small enough to diffuse through tissue, making it an excellent scaffold for a variety drug and gene delivery applications. 9−12 …”