Spray-Dried Particles of Nitric Oxide-Modified Glutathione for the Treatment of Chronic Lung Infection

Abstract

Antibiotic resistance in pathogenic bacteria has emerged as a big challenge to human and animal health and significant economy loss worldwide. Development of novel strategies to tackle antibiotic resistance is of the utmost priority. In this study, we combined glutathione (GSH), a master antioxidant in all mammalian cells, and nitric oxide, a proven biofilm-dispersing agent, to produce GSNO. The resazurin biofilm viability assay, crystal violet biofilm assay, and confocal microscopy techniques showed that GSNO disrupted biofilms of both P. aeruginosa PAO1 and multidrug resistant A. baumaunii (MRAB 015069) more efficiently than GSH alone. In addition, GSNO showed a higher reduction in biofilm viability and biomass when combined with antibiotics. This combination treatment also inhibited A. baumaunii (MRAB 015069) growth and facilitated human foreskin fibroblast (HFF-1) confluence and growth simultaneously. A potentially inhalable GSNO powder with reasonable aerosol performance and antibiofilm activity was produced by spray drying. This combination shows promise as a novel formulation for treating pulmonary bacterial infections.

Roles and current applications of S-nitrosoglutathione in anti-infective biomaterials

“…This activity is influenced by various factors, including the bacterial strain, GSNO dose and concentration, treatment duration, and NO release kinetics. Numerous studies have been conducted to evaluate the antibacterial properties of GSNO in various diseases ( Table 1 ), including pulmonary infection [ 40 , [45] , [46] , [47] ], cutaneous infection [ 23 , 48 , 49 ], cerebral malaria [ 50 ], cystic fibrosis [ 51 , 52 ], and digestive tract disease [ 53 ] ( Fig. 1 ).…”

“… Liu, C. [ 67 ] 2017 PCVAD NA/10 ​mM Porcine circovirus type 2 In-vitro 72 ​h In-vivo 7 ​d PK-15 ​cells BALB/c mice GSNO suppresses PCV2 infection in PK-15 ​cells and BALB/c mice. Das, T. [ 45 ] 2019 Chronic Lung Infection NA/10 ​mM P. aeruginosa /PAO1 24 ​h Human foreskin fibroblast/HFF-1 NA GSNO disrupted biofilms of both P. aeruginosa PAO1 and multidrug resistant A. baumaunii A. baumaunii/MRAB 015069

Fig. 1 Schematic illustrating the antibacterial activity of S-nitrosoglutathione.

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“…Adapted with permission from Ref. [ 45 ], copyright 2019 American Chemical Society. (c) The antibacterial property of GSNO for L. major and L. braziliensis .…”

“…The lungs are one of the most susceptible organs to bacteria, and bacterial lung infections result in more than 4 million deaths worldwide every year, and with the emerging antibiotic resistance it necessitates the development of novel therapeutic approaches [ 54 ]. Great efforts have been made to evaluate the therapeutic efficacy of GSNO in pulmonary infections [ 40 , [45] , [46] , [47] ]. Low levels of GSNO were insufficient to suppress the biosynthesis of alginate and exacerbation of cystic fibrosis in lungs infected with Pseudomonas aeruginosa [ 55 , 56 ].…”

3D Printing of Antibacterial Polymer Devices Based on Nitric Oxide Release from Embedded S-Nitrosothiol Crystals

“…NO inhibits adhesion and activation of platelets and thus prevents formation of thrombus on blood-contacting implants . NO also exerts potent and broad-spectrum antibacterial activities via multiple nitrosylation and oxidation mechanisms toward enzymes, proteins, DNA, and lipids. , Recently, exogenous NO alone or along with antibiotics has been found to significantly reduce the growth of multidrug-resistant bacteria in both planktonic and biofilm forms, representing a promising approach to combat the global threat of antimicrobial resistance. − Furthermore, NO has other functions such as vasodilation, anti-inflammation, pro-angiogenesis, and wound repair. , Indeed, release of exogenous NO has proven to improve the antimicrobial properties and biocompatibility of a wide array of medical products including those based on silicones and silicone copolymers. Some examples are urinary catheters, central venous catheters, extracorporeal circuits, vascular grafts, cannulas, and sensors. − …”