Nitric Oxide Stress as a Metabolic Flux

Nitric oxide (NO) is an antimicrobial metabolite produced by immune cells to prohibit infection. Due to its reactivity, NO has numerous reaction routes available to it in biological systems with some leading to cellular damage and others producing innocuous compounds. Pathogens have evolved resistance mechanisms toward NO, and many of these take the form of enzymes that chemically passivate the molecule. In essence, bacteria have channeled NO flux toward useful or harmless compounds, and away from pathways that damage cellular components. Pathogens devoid of detoxification enzymes have been found to have compromised survival in different infection models, which suggests that diverting flux away from NO defenses could be a viable antiinfective strategy. From this perspective, potentiation of NO stress mirrors challenges in metabolic engineering where researchers endeavor to divert flux away from endogenous pathways and toward those that produce desirable biomolecules. In this review, we cast NO stress as a metabolic flux and discuss how the tools and methodologies of metabolic engineering are well suited for analysis of this bacterial stress response. We provide examples of such interdisciplinary applications, discuss the benefits of considering NO stress from a flux perspective, as well as the pitfalls, and offer a vision for how metabolic engineering analyses can assist in deciphering the economics underlying bacterial responses to multistress conditions that are characteristic of the phagosomes of immune cells.