Chitosan derivatives co-delivering nitric oxide and methicillin for the effective therapy to the methicillin-resistant S. aureus infection

Carbohydr Polym. 2020 Apr 15:234:115928. doi: 10.1016/j.carbpol.2020.115928. Epub 2020 Jan 30.

Abstract

We developed a co-delivery system of nitric oxide (NO) and antibiotic for the antibiotic-resistant bacterial infection therapy. The NO could disperse the bacterial biofilms and convert the bacteria into an antibiotic-susceptible planktonic form. Using the chitosan-graft-poly(amidoamine) dendrimer (CS-PAMAM) as the co-delivery system, methicillin (MET) and NO were conjugated successively to form CS-PAMAM-MET/NONOate. The positive CS-PAMAM could efficiently capture the negatively charged bacteria and PAMAM provide abundant reaction points for high payloads of NO and MET. The CS-PAMAM-MET/NONOate displayed effective and combined antibacterial activity to the E. coli and S. aureus. Particularly, for the MET-resistant S. aureus (MRSA), the CS-PAMAM-MET/NONOate displayed the synergistic antibacterial activity. In vivo wound healing assays also confirmed that CS-PAMAM-MET/NONOate could heal the infection formed by MRSA and then accelerate the wound healing effectively. Moreover, CS-PAMAM-MET/NONOate showed no toxicity towards 3T3 cells in vitro and rats in vivo, providing a readily but high-efficient strategy to drug-resistant bacterial infection therapy.

Keywords: Antibacterial; Chitosan; Drug-resistant bacterial; Methicillin; Nitric oxide; PAMAM.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Biofilms / drug effects
  • Cell Survival / drug effects
  • Chitosan / chemistry
  • Chitosan / pharmacology*
  • Dendrimers / chemistry
  • Dendrimers / pharmacology
  • Drug Delivery Systems
  • Male
  • Methicillin / chemistry
  • Methicillin / pharmacology*
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Nitric Oxide / analysis
  • Nitric Oxide / metabolism
  • Nitric Oxide / pharmacology*
  • Particle Size
  • Polyamines / chemistry
  • Polyamines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / pathology
  • Surface Properties

Substances

  • Anti-Bacterial Agents
  • Dendrimers
  • Poly(amidoamine)
  • Polyamines
  • Nitric Oxide
  • Chitosan
  • Methicillin