Both toxic and beneficial effects of pyocyanin contribute to the lifecycle of Pseudomonas aeruginosa.

Pseudomonas aeruginosa, an opportunistic pathogen, produces redox-active pigments called phenazines. Pyocyanin (PYO, the blue phenazine) plays an important role during biofilm development. Paradoxically, PYO auto-poisoning can stimulate cell death and release of extracellular DNA (eDNA), yet PYO can also promote survival within biofilms when cells are oxidant-limited. Here, we identify the environmental and physiological conditions in planktonic culture that promote PYO-mediated cell death. We demonstrate that PYO auto-poisoning is enhanced when cells are starved for carbon. In the presence of PYO, cells activate a set of genes involved in energy-dependent defenses, including: (i) the oxidative stress response, (ii) RND efflux systems and (iii) iron-sulfur cluster biogenesis factors. P. aeruginosa can avoid PYO poisoning when reduced carbon is available, but blockage of adenosine triphosphate (ATP) synthesis either through carbon limitation or direct inhibition of the F0 F1 -ATP synthase triggers death and eDNA release. Finally, even though PYO is toxic to the majority of the population when cells are nutrient limited, a subset of cells is intrinsically PYO resistant. The effect of PYO on the producer population thus appears to be dynamic, playing dramatically different yet predictable roles throughout distinct stages of growth, helping rationalize its multifaceted contributions to biofilm development.