An effective response to respiratory inhibition by a excreted quinoline promotes fitness and survival in co-culture.

and are primary bacterial pathogens isolated from the airways of cystic fibrosis patients. produces secondary metabolites that negatively impact the fitness of , allowing to become the most prominent bacterium when the species are co-cultured. Some of these metabolites inhibit respiration. SrrAB is a staphylococcal two-component regulatory system (TCRS) that responds to alterations in respiratory status and helps transition between fermentative and respiratory metabolisms. We used mutant strains and chemical genetics to demonstrate that secondary metabolites, HQNO in particular, inhibit respiration, resulting in modified SrrAB stimulation. Metabolomic analyses found that the ratio of NAD to NADH increased upon prolonged culture with HQNO. Consistent with this, the activity of the Rex transcriptional regulator, which senses and responds to alterations in the NAD / NADH ratio, had altered activity upon HQNO treatment. The presence of SrrAB increased fitness when cultured with HQNO and increased survival when challenged with strains with a decreased ability to maintain redox homeostasis via fermentation had decreased fitness when challenged with HQNO and decreased survival when challenged with . These findings led to a model wherein secreted HQNO inhibits respiration, stimulating SrrAB, which promotes fitness and survival by increasing carbon flux through fermentative pathways to maintain redox homeostasis.