title: Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa-infected wounds.
abstract: Pseudomonas aeruginosa is a community-acquired, nosocomial pathogen that is an important cause of human morbidity and mortality; it is intrinsically resistant to several antibiotics and is capable of developing resistance to newly developed drugs via a variety of mechanisms. P aeruginosa's ubiquity and multidrug resistance (MDR) warrants the development of innovative methods that overcome its ability to develop resistance. We have previously described a nitric oxide-releasing nanoparticle (NO-np) platform that effectively kills gram-positive and gram-negative organisms in vitro and accelerates clinical recovery in vivo in murine wound and abscess infection models. We have also demonstrated that when glutathione (GSH) is added to NO-np, the nitroso intermediate S-nitrosoglutathione (GSNO) is formed, which has greater activity against P aeruginosa and other gram-negative organisms compared with NO-np alone. In the current study, we evaluate the potential of NO-np to generate GSNO both in vitro and in vivo in a murine excisional wound model infected with an MDR clinical isolate of P aeruginosa. Whereas NO-np alone inhibited P aeruginosa growth in vitro for up to 8 hours, NO-np+GSH completely inhibited P aeruginosa growth for 24 hours. Percent survival in the NO-np+GSH-treated isolates was significantly lower than in the NO-np (36.1% vs 8.3%; P=.004). In addition, NO-np+GSH accelerated wound closure in P aeruginosa-infected wounds, and NO-np+GSH-treated wounds had significantly lower bacterial burden when compared to NO-np-treated wounds (P<.001). We conclude that GSNO is easily generated from our NO-np platform and has the potential to be used as an antimicrobial agent against MDR organisms such as P aeruginosa.
authors: Department of Medicine, Division of Dermatology, Montefiore Medical Center, Bronx, NY, USA.
authors: Jason
authors: J
authors: Chouake
authors: David
authors: D
authors: Schairer
authors: Allison
authors: A
authors: Kutner
authors: David A
authors: DA
authors: Sanchez
authors: Joy
authors: J
authors: Makdisi
authors: Karin
authors: K
authors: Blecher-Paz
authors: Parimala
authors: P
authors: Nacharaju
authors: Chaim
authors: C
authors: Tuckman-Vernon
authors: Phil
authors: P
authors: Gialanella
authors: Joel M
authors: JM
authors: Friedman
authors: Joshua D
authors: JD
authors: Nosanchuk
authors: Adam J
authors: AJ
authors: Friedman
mesh_terms: D000818:Animals; D015169:Colony Count, Microbial; D024901:Drug Resistance, Multiple, Bacterial; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D026422:S-Nitrosoglutathione / Q000378:metabolism*; D012867:Skin / Q000382:microbiology; D013530:Surgical Wound Infection / Q000188:drug therapy* / Q000382:microbiology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D014665:Vasodilator Agents; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione