Quantitative Modeling Extends the Antibacterial Activity of Nitric Oxide

Abstract

Numerous materials have been developed to try and harness the antimicrobial properties of nitric oxide (NO). However, the short half-life and reactivity of NO have made precise, tunable delivery difficult. As such, conventional methodologies have generally relied on donors that spontaneously release NO at different rates, and delivery profiles have largely been constrained to decaying dynamics. In recent years, the possibility of finely controlling NO release, for instance with light, has become achievable and this raises the question of how delivery dynamics influence therapeutic potential. Here we investigated this relationship using Escherichia coli as a model organism and an approach that incorporated both experimentation and mathematical modeling. We found that the best performing delivery mode was dependent on the NO payload, and developed a mathematical model to quantitatively dissect those observations. Those analyses suggested that the duration of respiratory inhibition was a major determinant of NO-induced growth inhibition. Inspired by this, we constructed a delivery schedule that leveraged that insight to extend the antimicrobial activity of NO far beyond what was achievable by traditional delivery dynamics. Collectively, these data and analyses suggest that the delivery dynamics of NO have a considerable impact on its ability to achieve and maintain bacteriostasis.

Pseudomonas aeruginosa prioritizes detoxification of hydrogen peroxide over nitric oxide

“…The remaining parameters ( k NONOate , k autox , k La,NO ) were optimized using a non-linear least squares regression algorithm (lsqcurvefit) that minimized the sum of the squared residual errors (SSR) between measured data and simulation data. One hundred initializations were performed using randomized initial values within previously established bounds [ 27 ]. Evidence ratios (ER) were calculated, and all parameters sets with an ER less than 10 were accepted as viable.…”

Antimicrobial properties of diethylamine NONOate, a nitric oxide donor, against Escherichia coli: a pilot study

“…Inhaled NO (6.6 mM) was also effective in treating patients with pneumonia [ 66 ]. A quantitative modeling study evaluated continuous in vitro NO generation and determined that a concentration of at least 0.002 mM was required for optimal antibacterial activity [ 67 ]. Another in vitro study [ 68 ] examined NO gas (5.3 mM), which demonstrated efficacy against S. aureus with 6 cycles of NO gas every 30 min via continuous exposure; however, the antibacterial effects may have been due to the production of nitrogen dioxide (derived from NO when reacted with oxygen) or the formation of peroxynitrite [ 69 ] (a product of NO) and superoxide [ 70 ], both of which have been shown to be antibacterial.…”

Phagosome–Bacteria Interactions from the Bottom Up

“…Our group has created computational models to simulate stress networks in E. coli and P. aeruginosa (142,(167)(168)(169)(170)(171). The models are systems of ordinary differential equations that describe the change in concentration of biochemical species as a function of time in bioreactor experiments, where there are intra-and extracellular reaction networks, as well as gas-phase transport.…”