Synchronized switching of multiple toxin-antitoxin modules by (p)ppGpp fluctuation.

Area of Science:

• Microbiology
• Bacterial genetics
• Systems biology

Background:

• Toxin-antitoxin (TA) loci are prevalent in bacteria, including pathogens.
• TA systems are implicated in bacterial persister cell formation.
• The persistence phenotype exhibits functional redundancy among multiple TA systems.

Purpose of the Study:

• To investigate the interaction of multiple TA systems in bacterial growth-persistence switching.
• To model two scenarios of TA system noise: individual vs. coordinated.
• To understand the basis of functional redundancy in bacterial persistence.

Main Methods:

• Development of a mathematical model for TA system interactions.
• Simulation of two noise scenarios: independent TA system noise and coordinated noise via stress signals.
• Analysis of TA system dynamics and persistence switching.

Main Results:

• Individual TA system noise leads to strong dependence on the number of TA systems for exiting persistence.
• Coordinated noise, driven by stress signals like (p)ppGpp, reproduces the observed weak dependence and functional redundancy.
• The duration of high (p)ppGpp levels is a critical factor for persistence.

Conclusions:

• Coordinated noise, rather than individual system noise, explains the functional redundancy of multiple TA systems.
• The (p)ppGpp-mediated synchronized transition of TA systems is key to bacterial persistence.
• Understanding TA system dynamics is crucial for targeting pathogenic bacteria.