A broadly applicable, stress-mediated bacterial death pathway regulated by the phosphotransferase system (PTS) and the cAMP-Crp cascade

Jie Zeng, Yuzhi Hong, Ningqiu Zhao, Qianyu Liu, Weiwei Zhu, Lisheng Xiao, Weijie Wang, Miaomiao Chen, Shouqiang Hong, Liwen Wu, Yunxin Xue, Dai Wang, Jianjun Niu, Karl Drlica, Xilin Zhao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Recent work indicates that killing of bacteria by diverse antimicrobial classes can involve reactive oxygen species (ROS), as if a common, self-destructive response to antibiotics occurs. However, the ROS-bacterial death theory has been challenged. To better understand stress-mediated bacterial death, we enriched spontaneous antideath mutants of Escherichia coli that survive treatment by diverse bactericidal agents that include antibiotics, disinfectants, and environmental stressors, without a priori consideration of ROS. The mutants retained bacteriostatic susceptibility, thereby ruling out resistance. Surprisingly, pan-tolerance arose from carbohydrate metabolism deficiencies in ptsI (phosphotransferase) and cyaA (adenyl cyclase); these genes displayed the activity of upstream regulators of a widely shared, stress-mediated death pathway. The antideath effect was reversed by genetic complementation, exogenous cAMP, or a Crp variant that bypasses cAMP binding for activation. Downstream events comprised a metabolic shift from the TCA cycle to glycolysis and to the pentose phosphate pathway, suppression of stress-mediated ATP surges, and reduced accumulation of ROS. These observations reveal how upstream signals from diverse stress-mediated lesions stimulate shared, late-stage, ROS-mediated events. Cultures of these stable, pan-tolerant mutants grew normally and were therefore distinct from tolerance derived from growth defects described previously. Pan-tolerance raises the potential for unrestricted disinfectant use to contribute to antibiotic tolerance and resistance. It also weakens host defenses, because three agents (hypochlorite, hydrogen peroxide, and low pH) affected by pan-tolerance are used by the immune system to fight infections. Understanding and manipulating the PtsI-CyaA-Crp–mediated death process can help better control pathogens and maintain beneficial microbiota during antimicrobial treatment.

Original languageEnglish (US)
Article numbere2118566119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number23
DOIs
StatePublished - Jun 7 2022

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • cAMP-Crp transcription regulatory system
  • carbohydrate phosphotransferase system (PTS)
  • commonly shared death mechanism
  • reactive oxygen species (ROS)
  • stress-mediated killing

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