A shared alarmone–GTP switch controls persister formation in bacteria

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Abstract
Persisters are phenotypically switched bacteria that survive antibiotic exposure despite being genetically susceptible. Three pathways to persistence—triggered, spontaneous and antibiotic-induced—have been described, but the underlying molecular mechanisms are poorly understood. Here, we used antibiotic time–kill assays as well as single-cell approaches to show that all of the pathways depend on a common switch involving the alarmone guanosine tetra/penta-phosphate ((p)ppGpp) in Bacillus subtilis, each stemming from different alarmone synthetase(s). The accumulation of (p)ppGpp promotes persistence through depletion of intracellular GTP. We developed a fluorescent GTP reporter to visualize rare events of persister formation in wild-type bacteria, revealing a rapid switch from growth to dormancy in single cells as their GTP levels drop beneath a threshold. While a decrease in GTP in the bulk population slows growth and promotes antibiotic tolerance, (p)ppGpp drives persistence by driving rapid, switch-like decreases in GTP levels beneath the persister threshold in single cells. Persistence through alarmone–GTP antagonism is probably a widespread mechanism to survive antibiotics in B. subtilis and potentially beyond.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM127088)
  • Howard Hughes Medical Institute (EPI)
  • National Science Foundation (1715710)

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