A novel regulatory circuit to control indole biosynthesis protects Escherichia coli from nitrosative damages during the anaerobic respiration of nitrate.

Indole is a widely distributed microbial secondary metabolite. It mediates a broad range of physiological processes in both its producing and surrounding species. Yet, indole biosynthesis during the anaerobiosis of bacteria remains largely uncharacterized. Here, we find that while indole production is promoted during fermentation and anaerobic respiration of fumarate and trimethylamine N-oxide in E. coli, its biosynthesis is repressed during anaerobic respiration of nitrate especially during exponential growth. We show that expression of the indole biosynthetic operon tnaCAB is repressed under this condition by the two component systems NarXL and NarPQ in the global regulator FNR dependent manner. During stationary growth phase of nitrate respiration, indole biosynthesis is derepressed. However, cellular indole concentration remains low. We demonstrate that this is due to the rapid conversion of indole into mutagenic indole nitrosative derivatives under this condition. Consistent with this, a supplement of exogenous indole during nitrate respiration causes elevated mutation frequencies in E. coli cells lacking the detoxifying efflux genes mdtEF, and ectopic over-expression of tnaAB genes decreases the fitness of E. coli to this physiological condition. Together, these results suggest that indole production is tuned to the bioenergetics activities of E. coli to facilitate its adaptation and fitness.