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Surface ligand density of antibiotic-nanoparticle conjugates enhances target avidity and membrane permeabilization of vancomycin-resistant bacteria
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Hassan, Marwa, Ranzoni, Andrea, Phetsang, Wanida, Blaskovich, Mark A. T. and Cooper, Matthew A. (2017) Surface ligand density of antibiotic-nanoparticle conjugates enhances target avidity and membrane permeabilization of vancomycin-resistant bacteria. Bioconjugate Chemistry, 28 (2). pp. 353-361. doi:10.1021/acs.bioconjchem.6b00494 ISSN 1043-1802.
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Official URL: http://dx.doi.org/10.1021/acs.bioconjchem.6b00494
Abstract
Many bacterial pathogens have now acquired resistance toward commonly used antibiotics, such as the glycopeptide antibiotic vancomycin. In this study, we show that immobilization of vancomycin onto a nanometer-scale solid surface with controlled local density can potentiate antibiotic action and increase target affinity of the drug. Magnetic nanoparticles were conjugated with vancomycin and used as a model system to investigate the relationship between surface density and drug potency. We showed remarkable improvement in minimum inhibitory concentration against vancomycin-resistant strains with values of 13–28 μg/mL for conjugated vancomycin compared to 250–4000 μg/mL for unconjugated vancomycin. Higher surface densities resulted in enhanced affinity toward the bacterial target compared to that of unconjugated vancomycin, as measured by a competition experiment using a surrogate ligand for bacterial Lipid II, N-Acetyl-l-Lys-d-Ala-d-Ala. High density vancomycin nanoparticles required >64 times molar excess of ligand (relative to the vancomycin surface density) to abrogate antibacterial activity compared to only 2 molar excess for unconjugated vancomycin. Further, the drug-nanoparticle conjugates caused rapid permeabilization of the bacterial cell wall within 2 h, whereas no effect was seen with unconjugated vancomycin, suggesting additional modes of action for the nanoparticle-conjugated drug. Hence, immobilization of readily available antibiotics on nanocarriers may present a general strategy for repotentiating drugs that act on bacterial membranes or membrane-bound targets but have lost effectiveness against resistant bacterial strains.
Item Type: | Journal Article | ||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
Journal or Publication Title: | Bioconjugate Chemistry | ||||||||
Publisher: | American Chemical Society | ||||||||
ISSN: | 1043-1802 | ||||||||
Official Date: | 15 February 2017 | ||||||||
Dates: |
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Volume: | 28 | ||||||||
Number: | 2 | ||||||||
Page Range: | pp. 353-361 | ||||||||
DOI: | 10.1021/acs.bioconjchem.6b00494 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access |
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