Methicillin-resistant Staphylococcus aureus (MRSA) infection is now a prevalent medical crisis worldwide, especially due to the increasing incidence of skin infections such as impetigo and abscesses. Nitric oxide (NO) is a key component of innate host defense against pathogens such as MRSA, but the lack of effective delivery options has limited its therapeutic application. To address this deficiency, a composite hydrogel/glass nanotechnology capable of achieving controlled, concentration-specific, and stepwise release of NO was investigated as a potential new antibacterial agent in an in vivo MRSA abscess model. NO-releasing nanoparticles showed antibacterial activity against MRSA in in vitro cell culture and in vivo-induced abscesses. Patients with intramuscular MRSA abscesses are often hospitalized for intravenous antibiotics and may require interventional radiotherapy or surgery to drain the abscess or fluid buildup. It increases the overall cost of treatment and ultimately the associated suffering. With both the rising incidence of resistant isolates and cost of care, new therapies are needed in order to unburden the strain and difficulty of preventing the progression of and treating these deep tissue infections. NO is known to possess impressively broad antimicrobial activity due to both its inherent ability to inhibit growth and kill pathogens as well as its function as a potent immunostimulatory signaling molecule. However, as a highly reactive gas, NO has proven difficult to deliver in a convenient format and this has largely precluded its use, even in hospital settings. We have recently described a new nanoplatform comprised of nitric oxide releasing nanoparticles (NO-np). NO is generated within the particles through the thermally induced reduction of nitrite to NO. The unique make-up of the nanoparticles allows for long range electron and proton transfer, facilitating the redox chemistry. This technology is a novel NO generator without many of the shortcomings of organic nitrates such as nitroglycerin, the most commonly used NO-donor in clinical practice. The main limitation of organic nitrates is the loss of efficacy with prolonged continuous use. So-called 'nitrate tolerance' results from tissue thiol depletion, acquired desensitization of soluble guanylyl cyclases to NO, or increased degradation of cyclic guanosine monophosphate (GMP) by phosphodiesterases. NO-np is lacking an external reductant, many of these limitations maintain and in some cases improve efficacy. Many advantages of nanoparticle-based drug delivery have been recognized, including sustained and controlled drug release. The use of nanovehicles also enables the delivery of highly reactive and short-lived biomolecules such as nitric oxide. Nitric oxide (NO) has emerged as an interesting molecule due to its diverse and broad biological reactivity in biological systems. Named "Molecule of the Year" by Science in 1992, the effects of NO include: Regulation of vascular tone and permeability, antioxidants, neurotransmission, immune function, angiogenesis, and wound healing. NO has been shown to modulate the production and function of cytokines, chemokines and growth factors and thus has antibacterial and anti-inflammatory properties. Nitric oxide (NO)-releasing nanoparticles (NPs) have emerged as wound healing enhancers and novel antimicrobial agents that can circumvent antibiotic resistance. However, long-term NO release from NPs is still insufficient for clinical use. Nitric oxide (NO) is a diatomic free radical endogenously generated by NO synthase via oxidation of the amino acid L-arginine.

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