Persister cells are able to survive ROS accumulation induced by fungicidal drugs.

Fungicidal drugs induce ROS accumulation in the mitochondria, and persister cells appear to use several mechanisms to cope with the high amount of ROS. (A) Miconazole-induced ROS in the mitochondria is detoxified by the overexpression of several SODs. (B) AmB treatment results in ROS accumulation. This leads to calcium accumulation and activation of the calcineurin pathway, thereby increasing expression of CaCMA1 via Crz1. CaCMA1 expression results in decreased expression of TPS1 and TPS2 and concomitantly results in apoptosis. In order to survive the apoptotic response induced by ROS, persister cells need to break the apoptotic feedback loop. They do so by up-regulation of stress response proteins (indicated in green). First, up-regulation of Hsp21 in persister cells may result in an increased glycogen content that protects the cells from the oxidative stress. Second, Hsp90 is also up-regulated in persister cells. Paradoxically, Hsp90 also activates the apoptotic pathway by activation of the calcineurin pathway, and concomitantly inhibits Ras1-cAMP-PKA signaling, decreasing the apoptotic response. Therefore, depending on the conditions, Hsp90 may determine the cellular fate of biofilm cells under stringent oxidative stress conditions and may direct the cells to apoptosis or the persister cell state. Dashed bold lines: likely to occur in persister cells; bold lines: proven in persister cells; all other lines: proven to occur in cells undergoing apoptosis. AmB, Amphotericin B; Crz1, calcineurin responsive zinc finger 1; Hsp21, heat shock protein 21; PKA, protein kinase A; Ras1, rat sarcoma; ROS, reactive oxygen species; SOD, superoxide dismutase; Tps1, trehalose-6-phosphate synthase.