Bactericidal Efficacy of Nitric Oxide-Releasing Silica Nanoparticles

Abstract

The utility of nitric oxide (NO)-releasing silica nanoparticles as a novel antibacterial is demonstrated against Pseudomonas aeruginosa. Nitric oxide-releasing nanoparticles were prepared via co-condensation of tetraalkoxysilane with aminoalkoxysilane modified with diazeniumdiolate NO donors, allowing for the storage of large NO payloads. Comparison of the bactericidal efficacy of the NO-releasing nanoparticles to 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), a small molecule NO donor, demonstrated enhanced bactericidal efficacy of nanoparticle-derived NO and reduced cytotoxicity to healthy cells (mammalian fibroblasts). Confocal microscopy revealed that fluorescently-labeled NO-releasing nanoparticles associated with the bacteria, providing rationale for the enhanced bactericidal efficacy of the nanoparticles. Intracellular NO concentrations were measurable when the NO was delivered from nanoparticles as opposed to PROLI/NO. Collectively, these results demonstrate the advantage of delivering NO via nanoparticles for antimicrobial applications.Keywords nitric oxide; silica nanoparticle; antibacterial; bactericidal; cytotoxicity; reactive nitrogen species; reactive oxygen species Antibiotic resistance has resulted in bacterial infections becoming the most common cause of infectious disease-related death. 1,2 In the United States alone, nearly 2 million people per year acquire infections during a hospital stay, of which approximately 90,000 die. 2 The primary culprits behind such deadly infections are antibiotic-resistant pathogens, which are responsible for approximately 70% of all lethal nosocomial infections. The growing danger of life-threatening infections and the rising economic burden of resistant bacteria have created a demand for new antibacterial therapeutics.The use of nanoparticles as delivery vehicles for bactericidal agents represents a new paradigm in the design of antibacterial therapeutics. To date, most antibacterial nanoparticles have been engineered using traditional antibiotics that are either incorporated within the particle scaffold or attached to the exterior of the particle. In many cases, such particles have exhibited greater efficacy than their constituent antibiotics alone. For example, Gu et al. reported that vancomycin-capped gold nanoparticles exhibited a 64-fold improvement in efficacy over vancomycin alone. 3 Similarly, silver nanoparticles have schoenfisch@unc.edu. Supporting Information Available: Synthesis of FITC-modified silica nanoparticles, AFM analysis of nanoparticle dimensions, scavenging of NO by TSB, and confocal fluorescence microscopy images of PROLI/NO-treated P. aeruginosa cells. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript ACS Nano. Author manuscript; available in PMC 2013 February 13. shown greater antibacterial activity than silver ion (Ag + ) in solution due to the direct toxicity of the particles and tunable release of Ag + based on nanocomposite size. [4][...

Boosting TiO2-anatase antimicrobial activity: Polymer-oxide thin films

“…Comparison with reported results using Ag-based systems as commercial AgION coating stain steel (1.6 log-reduction/4 h) [38]; AgBr particles coating poly(vinyl pyridine)-NPVP (max. 4 logreduction) [39]; NO on silica (4 log-reduction/1.5 h) [40]; poly(-alkylammonium) coatings on polyurethanes (4.4 log-reduction/ 0.5 h) [41]; or simple chemicals like glutaraldehyde, formaldehyde, H 2 O 2 , phenol, cupric ascorbate or sodium hypochlorite (all below 6 log-reduction/0.5 h) [42] highlights the potential of our systems. As mentioned, the performance with E. faecalis is less studied but as a Gram positive bacterium has a thicker and more compact cell wall than the other microorganism of our study and thus is potentially more difficult to eliminate.…”

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

“…The utility of nanoparticles arises from their various physicochemical properties (e.g., hydrophobicity, charge, size), which can be tuned by varying synthetic precursors and procedures. Silica-and gold-based nanoparticles have been developed that release low or high levels of NO [136][137][138][139] and show effectiveness against biofilms [140]. Nanoparticles also offer the advantage that they can be combined with other active molecules, such as antimicrobial agents, e.g.…”

Heteroorganic molecules and bacterial biofilms: Controlling biodeterioration of cultural heritage

“…One example is the free radical nitric oxide (NO) that at low (nM) non-toxic concentrations is an important signalling molecule that induces biofilm dispersal. [11][12][13] Encouraging biofilms to disperse by beneficially interrupting these chemical signalling processes…”

“…Microbial cellular targets of reactive nitrogen intermediates (RNI). 13,261,262 High concentrations of NO however, induce nitrosative or oxidative stress events exerted by both NO and reactive nitrogen intermediates (RNI) derived from NO. 13,264,265 Reactive species such as dinitrogen trioxide (N 2 O 3 ) and peroxynitrite (ONOO -) have been shown to modify proteins, lipids and DNA through nitrosative stress events, such as thiol nitrosation, deamination of primary amines and nitrosamine formation; and oxidative stress events, such as lipid peroxidation, tyrosine nitration and oxidative DNA cleavage.…”

“…13,264,265 Reactive species such as dinitrogen trioxide (N 2 O 3 ) and peroxynitrite (ONOO -) have been shown to modify proteins, lipids and DNA through nitrosative stress events, such as thiol nitrosation, deamination of primary amines and nitrosamine formation; and oxidative stress events, such as lipid peroxidation, tyrosine nitration and oxidative DNA cleavage. 13,261,[266][267][268][269][270][271][272][273][274][275][276][277] The biological impact of NO-and RNI-mediated stress events are both regulatory and deleterious with the chemical impact on cell targets being implicated in a variety of processes including cell proliferation, cell survival, enzymatic inhibition, apoptosis control, and cell transformation. 265 An overview of some of the specific reactions and interactions of NO and RNI with biological targets is given in Scheme 2.…”