title: S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology.
abstract: Nitric oxide (NO), an essential agent of the innate immune system, exhibits multi-mechanistic antimicrobial activity. Previously, NO-releasing nanoparticles (NO-np) demonstrated increased antimicrobial activity when combined with glutathione (GSH) due to formation of S-nitrosoglutathione (GSNO), a transnitrosylating agent. To capitalize on this finding, we incorporated the thiol-containing ACE-inhibitor, captopril, with NO-np to form SNO-CAP-np, nanoparticles that both release NO and form S-nitrosocaptopril. In the presence of GSH, SNO-CAP-np demonstrated increased transnitrosylation activity compared to NO-np, as exhibited by increased GSNO formation. Escherichia coli and methicillin-resistant Staphylococcus aureus were highly susceptible to SNO-CAP-np in a dose-dependent fashion, with E. coli being most susceptible, and SNO-CAP-np were nontoxic in zebrafish embryos at translatable concentrations. Given SNO-CAP-np's increased transnitrosylation activity and increased E. coli susceptibility compared to NO-np, transnitrosylation rather than free NO is likely responsible for overcoming E. coli's resistance mechanisms and ultimately killing the pathogen.
  
  
  BACKGROUND
  This team of authors incorporated the thiol-containing ACE-inhibitor, captopril, into a nitric oxide releasing nanoparticle system, generating nanoparticles that both release NO and form S-nitrosocaptopril, with pronounced toxic effects on MRSA and E. coli in the presented model system.
authors.affiliation: Division of Dermatology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Breanne
authors.initials: B
authors.lastname: Mordorski
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Pelgrift
authors.affiliation: Division of Dermatology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Adler
authors.affiliation: Division of Dermatology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Krausz
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Alexandre Batista
authors.initials: AB
authors.lastname: da Costa Neto
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Liang
authors.affiliation: Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Gunther
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: Alicea
authors.initials: A
authors.lastname: Clendaniel
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA; School of Chemical, Biological and Environmental Engineering, Oregon State University, Corvallis, OR, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Harper
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Friedman
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Parimala
authors.initials: P
authors.lastname: Nacharaju
authors.affiliation: Division of Dermatology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA; Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: adfriedm@montefiore.org.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Friedman
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry; D002216:Captopril / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000890:Anti-Infective Agents; C060039:S-nitrosocaptopril; D009569:Nitric Oxide; D002216:Captopril; D005978:Glutathione
keywords: Antibacterial; E. coli; Nanotechnology; Nitric oxide; Nitrosothiols