Surface Ligand Density of Antibiotic-Nanoparticle Conjugates Enhances Target Avidity and Membrane Permeabilization of Vancomycin-Resistant Bacteria

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.

Drug delivery systems designed to overcome antimicrobial resistance

“…In a recent study, Hassan et al reported that the conjugation of vancomycin ( 34 ) with magnetic NPs significantly increased antimicrobial activity against vancomycin‐resistant bacteria, including S. aureus , E. faecium , and Enterococcus faecalis. The biological results demonstrated that the magnetic‐NP‐conjugated vancomycin ( 106 ) exhibited much smaller MICs against vancomycin‐resistant strains when compared to the free glycopeptide antibiotic ( 34 ) (MICs of 13‐28 and 250‐4000 µg/mL, respectively) . In addition, higher surface densities resulted in an enhanced affinity towards bacteria, with ( 106 ) causing rapid permeabilization through the bacterial cell wall within 2 hours, whereas no effect was observed with free vancomycin.…”

“…In addition, higher surface densities resulted in an enhanced affinity towards bacteria, with ( 106 ) causing rapid permeabilization through the bacterial cell wall within 2 hours, whereas no effect was observed with free vancomycin. The authors suggested that the immobilization of conventional antibiotics onto a nanometer‐scale solid surface with a controlled local density may re‐potentiate the action and increase the target affinity of the anti‐infective agents, which are currently clinically failing due to their toxicity or the resistance of micro‐organisms …”

“…In vivo (mouse model) 239 Better bioavailability More potent than the parent drugs (106) exhibited much smaller MICs against vancomycin-resistant strains when compared to the free glycopeptide antibiotic (34) (MICs of 13-28 and 250-4000 µg/mL, respectively). 236 In addition, higher surface densities resulted in an enhanced affinity towards bacteria, with (106) causing rapid permeabilization through the bacterial cell wall within 2 hours, whereas no effect was observed with free vancomycin. The authors suggested that the immobilization of conventional antibiotics onto a nanometer-scale solid surface with a controlled local density may re-potentiate the action and increase the target affinity of the anti-infective agents, which are currently clinically failing due to their toxicity or the resistance of micro-organisms.…”

“…The authors suggested that the immobilization of conventional antibiotics onto a nanometer-scale solid surface with a controlled local density may re-potentiate the action and increase the target affinity of the anti-infective agents, which are currently clinically failing due to their toxicity or the resistance of micro-organisms. 236 Yang et al successfully developed gentamycin-loaded mesoporous silica nanoparticles (MSNs) coated with lipid bilayers, harboring immobilized bacteria-targeting peptide UBI [29][30][31][32][33][34][35][36][37][38][39][40][41] (Gen@MSN-LU) to target intracellular S. aureus.…”

Application of Nanoparticle Technologies in the Combat against Anti-Microbial Resistance

“…Importantly, Brown’s study showed that both nanoparticulate formulations exhibited unique properties, which avoided the mechanisms deployed by bacteria that commonly result in the rise of multidrug resistance [ 79 ]. Hassan and colleagues reported the use of vancomycin-coated magnetic nanoparticles as anti-bacterial agents [ 80 ]. The novel formulation was tested against vancomycin resistant strains, exhibiting minimum inhibitory concentrations as low as 13–28 µg·mL −1 compared with 250–4000 µg·mL −1 for the free drug.…”