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

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