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. 2019 Aug 9;5(8):1327-1335.
doi: 10.1021/acsinfecdis.9b00016. Epub 2019 Jun 11.

Antibiofilm Efficacy of Nitric Oxide-Releasing Alginates against Cystic Fibrosis Bacterial Pathogens

Mona Jasmine R Ahonen  1 , Jamie M Dorrier  1 , Mark H Schoenfisch  1   2
Affiliations

Antibiofilm Efficacy of Nitric Oxide-Releasing Alginates against Cystic Fibrosis Bacterial Pathogens

Mona Jasmine R Ahonen et al. ACS Infect Dis. .

Abstract

Colonization of the lungs by biofilm-forming pathogens is a major cause of mortality in cystic fibrosis (CF). In CF patients, these pathogens are difficult to treat due to the additional protection provided by both the biofilm exopolysaccharide matrix and thick, viscous mucus. The antibiofilm efficacy of nitric oxide (NO)-releasing alginates was evaluated against Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, and methicillin-resistant S. aureus biofilms in both aerobic and anaerobic environments. Varying the amine precursor grafted onto alginate oligosaccharides imparted tunable NO storage (∼0.1-0.3 μmol/mg) and release kinetics (∼4-40 min half-lives) in the artificial sputum media used for biofilm testing. The NO-releasing alginates were highly antibacterial against the four CF-relevant pathogens, achieving a 5-log reduction in biofilm viability after 24 h of treatment, with biocidal efficacy dependent on NO-release kinetics. Aerobic biofilms required greater starting NO doses to achieve killing relative to the anaerobic biofilms. Relative to tobramycin (the minimum concentration of antibacterial agent required to achieve a 5-log reduction in viability after 24 h, MBEC24h, of ≥2000 μg/mL) and vancomycin (MBEC24h ≥ 1000 μg/mL), the NO-releasing alginates proved to be more effective (NO dose ≤ 520 μg/mL) regardless of growth conditions.

Keywords: alginates; antibiofilm; cystic fibrosis; nitric oxide.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Mark Schoenfisch is a cofounder, a member of the board of directors, and maintains financial interest in Vast Therapeutics, Inc. Vast commercializes macromolecular nitric oxide storage and release vehicles for respiratory indications.

Figures

Figure 1.
Figure 1.
Alkyl amine-modified alginates.
Figure 2.
Figure 2.
Real-time NO-release profiles for the first hour of release for (A) Alg5-DPTA/NO, (B) Alg5-PAPA/NO, and (C) Alg5-PAPA-DPTA/NO in PBS (black solid), ASM (gray solid), and DNA (black dash), and mucin (gray dash) solutions buffered at pH 6.5.
Figure 3.
Figure 3.
Nitric oxide dose for Alg5-DETA (light gray stripes), Alg5-DPTA/NO (solid light gray), Alg5-SPER/NO (dark gray stripes), Alg5-PAPA/NO (solid dark gray), Alg5-PAPA-DPTA/NO (black stripes) required to treat (A) aerobic and (b) anaerobic biofilms of P. aeruginosa, BCC, S. aureus, and MRSA compared to tobramycin (solid black). Studies consisted of at least three experiments with error bars representing the standard deviation.
Figure 4.
Figure 4.
Nitric oxide dose for Alg5-DETA (light gray stripes), Alg5-DPTA/NO (solid light gray), Alg5-SPER/NO (dark gray stripes), Alg5-PAPA/NO (solid dark gray), Alg5-PAPA-DPTA/NO (black stripes) required to treat (A) aerobic and (b) anaerobic biofilms of S. aureus and MRSA. All NO doses were compared to vancomycin (solid black). Studies consisted of at least three experiments with error bars representing the standard deviation.
Figure 5.
Figure 5.
Time-based bactericidal efficacy of Alg5-DPTA/NO (circle), Alg5-PAPA-DPTA/NO (triangle), Alg5-PAPA/NO (square), and tobramycin (cross). Comparison of all NO-releasing alginates at equivalent concentrations of (A) 4 mg/mL under aerobic conditions and (B) 2 mg/mL under anaerobic conditions. The MBEC24h values under aerobic and anaerobic conditions (2 mg/mL and 4 mg/mL, respectively) were used for tobramycin. Studies consisted of at least three experiments with error bars representing the standard deviation.
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