BacFlash signals acid-resistance gene expression in bacteria

Intracellular pH (pH_i) homeostasis is crucial for cellular functions and signal transduction across all kingdoms of life. In particular, bacterial pH_i homeostasis is important for physiology, ecology, and pathogenesis. Here we report an exquisite bacterial acid-resistance (AR) mechanism in which proton leak elicits a pre-emptive AR response. A single bacterial cell undergoes quantal electrochemical excitation, termed "BacFlash", which consists of membrane depolarization, transient pH_i rise, and bursting production of reactive oxygen species. BacFlash ignition is dictated by acid stress in the form of proton leak across the plasma membrane and the rate of BacFlash occurrence is reversely correlated with the pH_i buffering capacity. Through genome-wide screening, we further identify the ATP synthase F_o complex subunit a as the putative proton sensor for BacFlash biogenesis. Importantly, persistent BacFlash hyperactivity activates transcription of a panel of key AR genes and predisposes the cells to survive imminent extreme acid stress. These findings demonstrate a prototypical coupling between electrochemical excitation and nucleoid gene expression in prokaryotes.