Metabolic signals regulate resuscitation speed of antibiotic persister bacteria during infection

Han, J. M.; Lee, J.; Kim, J.; Lee, Y. Q.; Lee, D.; Lee, S. N.; Ko, D.; Kang, M.; Yu, T.; Jeong, K.; Chu, E.; Shin, B.; Koduru, L.; Bang, Y.; Han, D.; Kim, K.; Lee, D.-Y.; Kim, K.-W.; Hwang, G.-S.; Yeom, J.

doi:10.64898/2026.05.05.722882

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bioRxiv · 10.64898/2026.05.05.722882

Metabolic signals regulate resuscitation speed of antibiotic persister bacteria during infection

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Abstract

All living organisms adjust their metabolism in response to environmental changes. Under unfavorable conditions, organisms enter a state of dormancy by halting metabolism, enabling survival. Dormant bacteria become highly tolerant to antibiotics-a phenomenon called persistence. Here, we demonstrate that selective metabolic reprogramming controls the resuscitation speed of persister after antibiotic exposure. Using multi-omics and in silico modeling, we found that dormant bacteria reprogram metabolic pathways to modulate persister awakening. Accumulation of L-serine and reduction of arginine drive rapid resuscitation. L-serine promotes cysteine biosynthesis and motility while reducing energy metabolism to facilitate rapid resuscitation. In contrast, arginine slows regrowth from dormancy by enhancing ethanol-aldehyde and energy metabolism. L-serine and arginine can, respectively, promote or inhibit the regrowth of antibiotic persister cells in macrophages and mouse models, and regulate the awakening speed of Salmonella, E. coli, and methicillin-resistant Staphylococcus aureus (MRSA). These findings suggest new strategies to target chronic bacterial infections. TeaserL-serine speeds and arginine slows the awakening of antibiotic persisters, revealing targets for chronic infection.

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Han, J. M., Lee, J., Kim, J., Lee, Y. Q., Lee, D., Lee, S. N., Ko, D., Kang, M., Yu, T., Jeong, K., Chu, E., Shin, B., Koduru, L., Bang, Y., Han, D., Kim, K., Lee, D.-Y., Kim, K.-W., Hwang, G.-S., Yeom, J.. 2026-05-05. Metabolic signals regulate resuscitation speed of antibiotic persister bacteria during infection. https://doi.org/10.64898/2026.05.05.722882

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