Magnesium flux modulates ribosomes to increase bacterial survival

Abstract

Bacteria exhibit cell-to-cell variability in their resilience to stress, for example, following antibiotic exposure. Higher resilience is typically ascribed to "dormant" non-growing cellular states. Here, by measuring membrane potential dynamics of Bacillus subtilis cells, we show that actively growing bacteria can cope with ribosome-targeting antibiotics through an alternative mechanism based on ion flux modulation. Specifically, we observed two types of cellular behavior: growth-defective cells exhibited a mathematically predicted transient increase in membrane potential (hyperpolarization), followed by cell death, whereas growing cells lacked hyperpolarization events and showed elevated survival. Using structural perturbations of the ribosome and proteomic analysis, we uncovered that stress resilience arises from magnesium influx, which prevents hyperpolarization. Thus, ion flux modulation provides a distinct mechanism to cope with ribosomal stress. These results suggest new approaches to increase the effectiveness of ribosome-targeting antibiotics and reveal an intriguing connection between ribosomes and the membrane potential, two fundamental properties of cells.This work was supported by funding from The Spanish Ministry of Economy and Competitiveness and FEDER (project FIS2015-66503-C3-1-P) (to J.G.-O.), the ICREA Academia program (to J.G.-O.), and the Maria de Maeztu Program for Units of Excellence in Research and Development (Spanish Ministry of Economy and Competitiveness, MDM-2014-0370) (to J.G.-O.), the San Diego Center for Systems Biology (NIH P50 GM085764) (to G.M.S), National Institute of General Medical Sciences (R01 GM121888) (to G.M.S), and the Howard Hughes Medical Institute-Simons Foundation Faculty Scholars program (to G.M.S.)