Nitrosoglutathione Generating Nitric Oxide Nanoparticles as an ImprovedStrategy for Combating Pseudomonas aeruginosa - Infected Wounds

December 2012 | Volume 11 | Issue 12 | Original Article | 1471 | Copyright © 2012

Jason Chouake BA,a* David Schairer BA,a* Allison Kutner BA,a David A. Sanchez BS,b Joy Makdisi BS,a Karin Blecher-Paz MD,a Parimala Nacharaju PhD,c Chaim Tuckman-Vernon BS,cPhil Gialanella MS BS,d Joel M. Friedman MD PhD,c Joshua D. Nosanchuk MD,a,b and Adam J. Friedman MDa,c

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.

J Drugs Dermatol. 2012;11(12):1471-1477.

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INTRODUCTION

The aerobic, gram-negative bacterium Pseudomonas aeruginosa is an important cause of both communityacquired and hospital-acquired infections.1-3 Community-acquired infections include, but are not limited to, ulcerative keratitis (usually associated with contact lens use), otitis externa (typically in immunocompromised hosts such as those with diabetes mellitus), and skin and soft tissue infections.4-6 Hospitalized patients may be colonized with P aeruginosa on admission or may acquire P aeruginosa during their hospital stay. P aeruginosa can be isolated from nearly any conceivable source within hospitals.3 In addition, specific patient populations such as those with cystic fibrosis or acquired immunosuppression, who suffer from chronic sinopulmonary colonization and recurrent infections from P aeruginosa , are known to have associated high morbidity and mortality when compared with other bacterial pathogens.7-9

Of extreme concern are the antimicrobial resistance trends that have been noted in large databases of nosocomial P aeruginosa isolates. P aeruginosa is intrinsically resistant to many antibacterials, including many β-lactams, the macrolides, the tetracyclines, cotrimoxazole (trimethoprim/sulfamethoxazole), and most fluoroquinolones.2,9-14 P aeruginosa is quite capable of developing resistance to any of the newer agents entering the market, often under the influence of previous antibacterial exposure. General mechanisms of antibacterial resistance include blockade of entry, active efflux from the cell, enzymatic degradation, and target structure alteration.15 P aeruginosa is capable of affecting any of these mechanisms in the development of resistance.

In light of this evolving medical crisis, it is of the utmost importance to develop new approaches with multiple mechanisms of action, for which it is difficult for pathogens to develop resistance. Nitric oxide (NO) represents one such avenue. Nitric oxide is a vital component of mammalian host defense, produced in and by cells comprising the innate immune system, most importantly macrophages, and can inhibit and/or kill a broad range of microorganisms.16,17 The mechanisms through

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