Surface ligand density of antibiotic-nanoparticle conjugates enhances target avidity and membrane permeabilization of vancomycin-resistant bacteria

Hassan, Marwa Hussain Ali, Ranzoni, Andrea, Phetsang, Wanida, Blaskovich, Mark A. T. and Cooper, Matthew A. (2016) Surface ligand density of antibiotic-nanoparticle conjugates enhances target avidity and membrane permeabilization of vancomycin-resistant bacteria. Bioconjugate Chemistry, 28 2: 353-361. doi:10.1021/acs.bioconjchem.6b00494


Author Hassan, Marwa Hussain Ali
Ranzoni, Andrea
Phetsang, Wanida
Blaskovich, Mark A. T.
Cooper, Matthew A.
Title Surface ligand density of antibiotic-nanoparticle conjugates enhances target avidity and membrane permeabilization of vancomycin-resistant bacteria
Journal name Bioconjugate Chemistry   Check publisher's open access policy
ISSN 1043-1802
1520-4812
Publication date 2016-12-13
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acs.bioconjchem.6b00494
Open Access Status Not yet assessed
Volume 28
Issue 2
Start page 353
End page 361
Total pages 9
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Subject 1305 Biotechnology
1502 Bioengineering
2204 Biomedical Engineering
3004 Pharmacology
3003 Pharmaceutical Science
1605 Organic Chemistry
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.
Keyword Biochemical Research Methods
Biochemistry & Molecular Biology
Chemistry, Multidisciplinary
Chemistry, Organic
Biochemistry & Molecular Biology
Chemistry
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP631632
094977/Z/10/Z
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 05 Jan 2017, 01:46:07 EST by Susan Allen on behalf of Institute for Molecular Bioscience