TY - JOUR

T1 - One-step synthesis of high-density peptide-conjugated gold nanoparticles with antimicrobial efficacy in a systemic infection model

AU - Rai, Akhilesh

AU - Pinto, Sandra

AU - Velho, Tiago R

AU - Ferreira, André F

AU - Moita, Catarina

AU - Trivedi, Urvish

AU - Evangelista, Marta

AU - Comune, Michela

AU - Rumbaugh, Kendra P.

AU - Simões, Pedro N

AU - Moita, Luís

AU - Ferreira, Lino

N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.

PY - 2016

Y1 - 2016

N2 - The increase in antibiotic drug resistance and the low number of new antibacterial drugs approved in the last few decades requires the development of new antimicrobial strategies. Antimicrobial peptides (AMPs) are very promising molecules to fight microbial infection since they kill quickly bacteria and, in some cases, target bacterial membrane. Although some AMPs may be stable against proteolytic degradation by chemical modification, in general, low AMP activity and stability in the presence of serum and proteolytic enzymes as well as their cytotoxicity have impaired their clinical translation. Here, we describe a one-step methodology to generate AMP-conjugated gold nanoparticles (Au NPs), with a high concentration of AMPs (CM-SH) (≈240 AMPs per NP), controlled size (14 nm) and low polydispersity. AMP-conjugated Au NPs demonstrated higher antimicrobial activity and stability in serum and in the presence of non-physiological concentrations of proteolytic enzymes than soluble AMP, as well as low cytotoxicity against human cells. Moreover, the NPs demonstrated high antimicrobial activity after in vivo administration in a chronic wound and in an animal model of systemic infection.

AB - The increase in antibiotic drug resistance and the low number of new antibacterial drugs approved in the last few decades requires the development of new antimicrobial strategies. Antimicrobial peptides (AMPs) are very promising molecules to fight microbial infection since they kill quickly bacteria and, in some cases, target bacterial membrane. Although some AMPs may be stable against proteolytic degradation by chemical modification, in general, low AMP activity and stability in the presence of serum and proteolytic enzymes as well as their cytotoxicity have impaired their clinical translation. Here, we describe a one-step methodology to generate AMP-conjugated gold nanoparticles (Au NPs), with a high concentration of AMPs (CM-SH) (≈240 AMPs per NP), controlled size (14 nm) and low polydispersity. AMP-conjugated Au NPs demonstrated higher antimicrobial activity and stability in serum and in the presence of non-physiological concentrations of proteolytic enzymes than soluble AMP, as well as low cytotoxicity against human cells. Moreover, the NPs demonstrated high antimicrobial activity after in vivo administration in a chronic wound and in an animal model of systemic infection.

KW - Animals

KW - Anti-Infective Agents/chemistry

KW - Antimicrobial Cationic Peptides/chemistry

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Escherichia coli/drug effects

KW - Gold/chemistry

KW - Humans

KW - Klebsiella pneumoniae/drug effects

KW - Metal Nanoparticles/chemistry

KW - Mice

KW - Mice, Inbred C57BL

KW - Peripheral Blood Stem Cells/drug effects

KW - Pseudomonas aeruginosa/drug effects

KW - Staphylococcus aureus/drug effects

U2 - 10.1016/j.biomaterials.2016.01.051

DO - 10.1016/j.biomaterials.2016.01.051

M3 - Journal article

C2 - 26866877

VL - 85

SP - 99

EP - 110

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -