Authors
Lonergan, Z. R., Weisflog, S. L., Scurria, M., Li, J., Thalhammer, K., Gutierrez, O., Conway, S. J., Newman, D. K.
Abstract
The radical nitric oxide (NO) is short-lived but has imprinted itself on many aspects of physiology and disease. NO's rapid production and consumption, coupled with its intrinsic reactivity, drive its biological importance; thus, defining mechanisms and targets of NO reactivity is necessary to assess its fate and impact. Cellular small molecules are a major class of NO-reactive targets, possessing a variety of molecular functionalities that can react with NO. Yet the capacity for secreted small molecules to react with NO, as well as the biological consequences of such reactivity, have received little attention. Here, we explore the reactivity of NO with phenazine metabolites, microbially-derived secreted small molecules that possess antibiotic properties and can modulate their microenvironment. Using Pseudomonas aeruginosa as a model phenazine producer, we find that NO reacts with specific phenazines to yield stable, chemically-distinct products. These chemical transformations significantly attenuate phenazine antibiotic properties, including against the phenazine nonproducer Staphylococcus aureus, a competitor with P. aeruginosa for niches in the context of infection. By contrast, P. aeruginosa experiences rapid loss in viability when phenazines and NO react. This toxicity occurs even in the presence of S. aureus, which displays resistance to nitrosylated phenazines, implicating a specific toxicity dependent on the formation of the phenazine-NO adduct. These findings highlight the capacity of NO to transform metabolite activity and suggest that NO can tune microbial interactions in complex environments by a mechanism of action hitherto unappreciated.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Nov 2025.
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