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<p>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 <i>Bacillus subtilis</i>, 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 <i>B. subtilis</i> and potentially beyond.</p>

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A shared alarmone–GTP switch controls persister formation in bacteria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月15日

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  • Danny K. Fung,
  • Jessica T. Barra,
  • Jin Yang,
  • Jeremy W. Schroeder,
  • Fukang She,
  • Megan Young,
  • David Ying,
  • David M. Stevenson,
  • Daniel Amador-Noguez,
  • Jue D. Wang

摘要

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.