Multisite phosphorylation drives phenotypic variation in (p)ppGpp synthetase-dependent antibiotic tolerance.

Area of Science:

• Microbiology
• Molecular Biology
• Systems Biology

Background:

• Phenotypic variability within isogenic cell populations has physiological consequences.
• Individual bacteria can exhibit differing antibiotic tolerance, but the regulation of this variability is unclear.

Purpose of the Study:

• To investigate the regulation of extrinsic noise in the Bacillus subtilis sasA gene.
• To understand how this regulation impacts antibiotic tolerance in bacterial populations.

Main Methods:

• Analysis of sasA gene expression in Bacillus subtilis.
• Investigated regulation by multisite phosphorylation of the transcription factor WalR.
• Utilized a predictive model to assess the impact of sasA expression on antibiotic survival.

Main Results:

• The sasA gene exhibits high levels of extrinsic noise in expression.
• sasA expression is regulated by multisite phosphorylation of WalR, involving PrkC/PrpC and WalK.
• High sasA expression correlates with increased antibiotic tolerance, particularly in outlier cells.

Conclusions:

• Multisite phosphorylation is a key mechanism for regulating phenotypic variability in antibiotic tolerance.
• This regulatory pathway allows bacteria to control outlier cells with enhanced survival traits.
• Targeting this regulation could be a strategy to manage antibiotic resistance.