Model-driven identication of dosing regimens that maximize the antimicrobial activity of nitric oxide

Jonathan L. Robinson, Richard V. Miller, Mark P. Brynildsen

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The antimicrobial properties of nitric oxide (NO{filled circle}) have motivated the design of NO{filled circle}-releasing materials for the treatment and prevention of infection. The biological activity of NO{filled circle}is dependent on its delivery rate, suggesting that variable antimicrobial effects can result from identical NO{filled circle}payloads dosed at different rates. Using a kinetic model of the Escherichia coli NO{filled circle}biochemical network, we investigated the relationship between NO{filled circle}delivery rate, payload, and cytotoxicity, as indicated by the duration of respiratory inhibition. At low NO{filled circle}payloads, the model predicted greater toxicity with rapid delivery, while slower delivery was more effective at higher payloads. These predictions were conrmed experimentally, and exhibited quantitative agreement with measured O2 and NO{filled circle}concentrations, and durations of respiratory inhibition. These results provide important information on key design parameters in the formulation of NO{filled circle}-based therapeutics, and highlight the utility of a model-based approach for the analysis of dosing regimens.

Original languageEnglish (US)
Pages (from-to)12-18
Number of pages7
JournalMetabolic Engineering Communications
Volume1
Issue number1
DOIs
StatePublished - 2014

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biomedical Engineering

Keywords

  • Antimicrobial
  • Escherichia coli
  • Hmp
  • Kinetic model
  • Nitric oxide
  • Nitric oxide dioxygenase
  • Respiration

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