Nitric oxide tunes secreted metabolite bioactivity

Area of Science:

• Microbiology
• Chemical Biology
• Biochemistry

Background:

• Nitric oxide (NO) is a crucial signaling molecule involved in numerous physiological and pathological processes.
• Small molecules are key targets of NO reactivity, but the interaction between secreted microbial metabolites and NO is underexplored.
• Phenazines are microbially-derived secondary metabolites with antibiotic properties that modulate the microenvironment.

Purpose of the Study:

• To investigate the reactivity of NO with phenazine metabolites.
• To determine the biological consequences of NO-phenazine interactions.
• To elucidate the role of NO in modulating microbial interactions via phenazine modification.

Main Methods:

• Utilized *Pseudomonas aeruginosa* as a model organism for phenazine production.
• Analyzed the chemical products formed from the reaction of NO with specific phenazines.
• Assessed the impact of NO-induced phenazine modification on antibiotic activity against *Staphylococcus aureus*.
• Evaluated the toxicity of NO-phenazine reactions on *P. aeruginosa* viability.

Main Results:

• NO reacts with specific phenazines to form stable, distinct chemical products.
• These chemical transformations significantly reduce the antibiotic efficacy of phenazines.
• NO-mediated phenazine modification leads to rapid cell death in *P. aeruginosa*, independent of *S. aureus* resistance to nitrosylated phenazines.
• A specific toxicity mechanism linked to the phenazine-NO adduct formation was identified.

Conclusions:

• Nitric oxide can chemically transform secreted microbial metabolites, altering their biological functions.
• NO-induced modification of phenazines attenuates their antibiotic properties and impacts microbial competition.
• NO plays a previously unrecognized role in regulating microbial interactions by modulating metabolite activity.