Vancomycin or polymyxin B each represents the preferred ligand for targeting Gram(+) or Gram(-) bacteria, respectively. However, emerging bacterial species show resistance to such antibacterial ligands through reprograming in cell wall structure. This talk discloses the applicatiob of multivalent design as an effective strategy for overcoming affinity limitation in bacteria-targeting nano delivery systems. First, we designed a series of fifth generation (G5) poly(amido amine) (PAMAM) dendrimers tethered with polymyxin B or vancomycin at  different valencies. Second, we performed surface plasmon resonance studies to determine their binding avidity to two cell wall models, each made with either D-Ala-D-Ala (or D-Ala-D-Lac) peptide for Gram(+) cell wall or lipopolysaccharide for Gram(-) cell wall. Each of these conjugates showed remarkable enhancement in avidity in the targeted cell wall model with at least four orders of magnitude greater than free ligand. In addition, some of the vancomycin-conjugated dendrimers showed dual avidity by being able to bind both Gram(+) and Gram(-) cell wall models. Third, we investigated whether the ability of the dendrimer binding to the model surface is consistent with its binding ability to bacterial cells in vitro by imaging with confocal fluorescent microscopy. Finally, we explored the utility of these bacteria-targeted dendrimers for controlled delivery of other antibiotic molecules and also for real-time, rapid bacterial isolation and enumeration. In summary, this talk describes the multivalent design, biophysical investigations and core-shell nanofabrication of PAMAM dendrimer conjugates for bacteria targeted biomedical applications.

Multivalent dendrimer nanoplatform for targeting bacterial surface

248th National Meeting (2014)

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