title: 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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. skchoi@umich.edu
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Andrzej
authors.initials: A
authors.lastname: Myc
authors.forename: Justin Ezekiel
authors.initials: JE
authors.lastname: Silpe
authors.forename: Madhuresh
authors.initials: M
authors.lastname: Sumit
authors.forename: Pamela Tinmoi
authors.initials: PT
authors.lastname: Wong
authors.forename: Kelly
authors.initials: K
authors.lastname: McCarthy
authors.forename: Ankur M
authors.initials: AM
authors.lastname: Desai
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Mark M Banaszak
authors.initials: MM
authors.lastname: Holl
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Orr
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D006094:Gram-Positive Bacteria / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008422:Materials Testing; D053769:Nanocapsules / Q000008:administration & dosage*; D014640:Vancomycin / Q000008:administration & dosage* / Q000737:chemistry*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D050091:Dendrimers; D053769:Nanocapsules; C104700:PAMAM Starburst; D014640:Vancomycin